Value through Innovation22 May 2013

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Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

164 publications regarding Chemistry
  • Author:
    Thai K; Langdon S M; Bilodeau F; Gravel M
    Title:
    Highly chemo- and enantioselective cross-benzoin reaction of aliphatic aldehydes and ?-ketoesters
    Source:
    Org Lett 15 (9), 2214-2217 (2013)
    Abstract:
    An electron-deficient, valine-derived triazolium salt is shown to catalyze a highly chemo- and enantioselective cross-benzoin reaction between aliphatic aldehydes and ?-ketoesters. This methodology represents the first high yielding and highly enantioselective intermolecular cross-benzoin reaction using an organocatalyst (up to 94% ee). Further diastereoselective reduction of the products gives access to densely oxygenated compounds with high chemo- and diastereoselectivity. © 2013 American Chemical Society.
  • Author:
    Lu B Z; Wei H X; Zhang W; Dufour M; Li G; Farina V; Senanayake C H
    Title:
    One-pot and regiospecific synthesis of 2,3-disubstituted indoles from 2-bromoanilides via consecutive palladium-catalyzed sonogashira coupling, amidopalladation, and reductive elimination
    Source:
    J Org Chem 78 (9), 4558-4562 (2013)
    Abstract:
    A practical one-pot and regiospecific three-component process for the synthesis of 2,3-disubstituted indoles from 2-bromoanilides was developed via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination. © 2013 American Chemical Society.
  • Author:
    Firestone, R A
    Title:
    The low energy of concert in many symmetry-allowed cycloadditions supports a stepwise-diradical mechanism
    Source:
    Int J Chem Kinet 45 (7), 415-428 (2013)
    Abstract:
    The thesis of this paper is that orbital symmetry allowedness does not guarantee concert. The activation energy (Ea) for concerted Diels-Alder and 1,3-dipolar cycloadditions must be substantially lower than that for a stepwise-diradical pathway because the diradical has two fewer bonding electrons than anything on the concerted reaction coordinate, including the transition state. Two bonding electrons provide tens of kcal/mol of stabilization. The difference between the experimental Ea and that for diradicals is called the energy of concert (Econ). If experiment represents concert, Econ must be large, and if it represents diradicals Econ will be very small. In this paper, 42 examples are adduced in which firm experimental data show that Econ = 0. These cycloadditions cannot be concerted. While concert remains possible for all cycioadditions not proven stepwise, there is none with compelling evidence for concert. © 2013 Wiley Periodicals, Inc.
  • Author:
    Reeves J T; Fandrick D R; Tan Z; Song J J; Rodriguez S; Qu B; Kim S; Niemeier O; Li Z; Byrne D; Campbell S; Chitroda A; Decroos P; Fachinger T; Fuchs V; Connella N C; Grinberg N; Haddad N; Jäger B; Lee H; Lorenz J C; Ma S; Narayanan B A Nummy L J; Premasiri A; Roschangar F; Sarvestani M; Shen S; Spinelli E; Sun X; Varsolona R J; Yee N; Brenner M; Senanayake CH
    Title:
    Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4
    Source:
    J Org Chem 78 (8), 3616-2635 (2013)
    Abstract:
    The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size. © 2013 American Chemical Society.
  • Author:
    Fandrick D R; Reeves J T; Bakonyi J M; Nyalpatla P R; Tan Z; Niemeier O; Akalay D; Fandrick K R; Wohlleben W; Ollenberger S; Song J J; Sun X; Qu B; Haddad N; Sanyal S; Shen S; Ma S; Byme D; Chitroda A; Fuchs V; Narayanan B A; Grinberg N; Lee N; Vrenner M; Senanayake C H
    Title:
    Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate
    Source:
    J Org Chem 78 (8), 3592-3615 (2013)
    Abstract:
    The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones. © 2013 American Chemical Society.
  • Author:
    Riniker S; Barandun L J; Diederich F; Krämer O; Steffen A; Van Gusteren W F
    Title:
    Free enthalpies of replacing water molecules in protein binding pockets
    Source:
    J Comput Aided Mol Des 26 (12), 1293-1309 (2012)
    Abstract:
    Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate the displacement of water molecules by an apolar probe in the binding pocket of two proteins, cyclin-dependent kinase 2 and tRNA-guanine transglycosylase, using the method of enveloping distribution sampling (EDS) to obtain free enthalpy differences. In both cases, a ligand core is placed inside the respective pocket and the remaining water molecules are converted to apolar probes, both individually and in pairs. The free enthalpy difference between a water molecule and a CH3 group at the same location in the pocket in comparison to their presence in bulk solution calculated from EDS molecular dynamics simulations corresponds to the binding free enthalpy of CH3 at this location. From the free enthalpy difference and the enthalpy difference, the entropic contribution of the displacement can be obtained too. The overlay of the resulting occupancy volumes of the water molecules with crystal structures of analogous ligands shows qualitative correlation between experimentally measured inhibition constants and the calculated free enthalpy differences. Thus, such an EDS analysis of the water molecules in the binding pocket may give valuable insight for potency optimization in drug design. © 2012 Springer Science+Business Media Dordrecht.
  • Author:
    Reeves J T; Tan Z; Herbage M A; Han Z S; Marsini M A; Li Z; Li G; Xu Y; Fandrick K R; Gonella N C; Campbell S; Ma S; Grinberg N; Lee H; Lu B Z; Senanayake C H
    Title:
    Carbamoyl anion addition to N -sulfinyl imines: Highly diastereoselective synthesis of ?-amino amides
    Source:
    J Am Chem Soc 135 (15), 5565-5568 (2013)
    Abstract:
    Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide alpha -amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to alpa-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with ?2 coordination of lithium by the carbonyl group. © 2013 American Chemical Society.
  • Author:
    Fandrick K R; Ogikubo J; Fandrick D R; Patel N D; Saha J; Lee H; Ma S; Grinberg N; Busacca C A; Senanayake C H
    Title:
    Copper-catalyst-controlled site-selective allenylation of ketones and aldehydes with propargyl boronates
    Source:
    Org Lett 15 (6), 1214-1217 (2013)
    Abstract:
    A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity. © 2013 American Chemical Society.
  • Author:
    Taylor S J; Soleymanzadeh F; Muegge I; Akiba I; Taki N; Ueda S; Mainolfi E; Eldrup A B
    Title:
    Deconstruction of sulfonamide inhibitors of the urotensin receptor (UT) and design and synthesis of benzylamine and benzylsulfone antagonists
    Source:
    Bioorg Med Chem Lett 23 (7), 2177-2180 (2013)
    Abstract:
    Potent small molecule antagonists of the urotensin receptor are described. These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor. The series of benzylamine and benzylsulfone antagonists herein reported display a combination of nanomolar molecular and cellular potency as well as acceptable in vitro permeability and metabolic stability. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    James C A; DeRoy P; Duplessis M; Edwards P J; Halmos T; Minville J; Morency L; Morin S Simoneau B; Tremblay M; Bethell R; Cordingley M; Duan J; Lamorte L; Pelletier A; Rajotte D; Salois P; Tremblay S; Sturino C F
    Title:
    Nucleotide competing reverse transcriptase inhibitors: Discovery of a series of non-basic benzofurano[3,2-d]pyrimidin-2-one derived inhibitors
    Source:
    Bioorg Med Chem Lett Article in Press (2013)
    Abstract:
    A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties. © 2013.
  • Author:
    Tremblay M; Bethell R C; Cordingley M G; DeRoy P; Duan J; Duplessis M; Edwards P J; Faucher A M; Halmos T; James C A; Kuhn C; Lacoste J E; Lamorte L; LaPlante S R; Malenfant E; Minville J; Moremcy L; Morin S; Rajotte D; Salois P; Simoneau B; Tremblay S; Sturino C F
    Title:
    Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors
    Source:
    Bioorg Med Chem Lett Article in Press (2013)
    Abstract:
    Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Duplessis M; Morency L; James C; Minville J; Deroy P; Morin S; Thavonekham B; Tremblay M; Halmos T; Simoneau B; Bousquet Y; Sturino C
    Title:
    Multi-gram synthesis of a nucleotide-competing reverse transcriptase inhibitor
    Source:
    Tetrahedron Lett Article in Press (2013)
    Abstract:
    An efficient multi-gram synthesis of a nucleotide-competing reverse transcriptase inhibitor is reported. The synthesis features a chiral auxiliary-assisted alcohol resolution, a Mitsunobu reaction involving a carbamate, followed by a lithium-iodide exchange/Weinreb ketone synthesis tandem. These chemical transformations were optimized in order to increase the yield of the synthesis. The route is concluded by a late-stage palladium-catalyzed cyanation followed by a pyrimidine-2-one ring formation. © 2013.
  • Author:
    Blaschka T; Hassa H
    Title:
    Second osmotic virial coefficients and aggregation of monoclonal antibodies by static laser light scattering
    Source:
    Z Phys Chem 227 (2-3), 333-343 (2013)
    Abstract:
    The second osmotic virial coefficient and the apparent molar mass of two human and one mouse monoclonal antibodies were measured in different aequeous buffer solutions which also contained sodium chloride or ammonium sulfate, respectively, by static laser light scattering in batch mode. The apparent molar mass indicates aggregation. At a constant pH value of 6.5 the sodium chloride concentration was varied from 0 to 2 M and the ammonium sulfate concentration from 0 to 0.8 M, respectively. A 20 mM sodium-phosphate buffer was used for all experiments. Furthermore the pH value was varied without adding additional salt from 4.5 to 10. The results of the salt dependency are in line with the Hofmeister-series. The results of the pH dependency correspond to the net charge of the molecules. © by Oldenbourg Wissenschaftsverlag, München.
  • Author:
    Mahut M; Gargano A; Schuchnigg H; Lindner W; Lämmernhofer M
    Title:
    Chemoaffinity material for plasmid DNA analysis by high-performance liquid chromatography with condition-dependent switching between isoform and topoisomer selectivity
    Source:
    Anal Chem 85 (5), 2913-2920 (2013)
    Abstract:
    Plasmid DNA may exist in three isoforms, the linear, open-circular (oc, "nicked"), and covalently closed circular (ccc, " supercoiled") form. We have recently reported on the chromatographic separation of supercoiled plasmid topoisomers on cinchona-alkaloid modified silica-based stationary phases. Herein, we present a selectivity switching mechanism to achieve separation of isoforms and/or supercoiled topoisomers using the very same chromatographic column and system. While salt gradient elution facilitates topoisomer separation, the supercoiled species are eluting as a single peak upon elution by a mixed pH and organic modifier gradient, still well separated from the other isoforms. We have found that a mobile phase pH value near the pI of the zwitterionic adsorbent surface leads to full recovery of all plasmid DNA isoforms, which is a major issue when using anion exchange-based resins. Furthermore, the observed elution pattern, oc < linear < ccc, is constant upon changes of mobile phase composition, gradient slope, and plasmid size. The remarkable isoform selectivity found on quinine-based selectors is explained by van't Hoff plots, revealing a different binding mechanism between the supercoiled plasmid on one hand and the oc and linear isoforms on the other hand. © 2013 American Chemical Society.
  • Author:
    Busacca C A; Qu B; Farber E; Haddad N; Gret N; Saha A K; Eriksson M C; Wu J P; Fandrick K R; Han S; Grinberg N; Ma S; Lee H; Li Z; Spinelli M; Gold A; Wang Z; Wang G; Wipf P; Senanayaka C H
    Title:
    [2,3]-Sigmatropic rearrangements of 2-phosphineborane 2-propen-1-ols: Rapid access to enantioenriched diphosphine monoxide derivatives
    Source:
    Org Lett 15 (5), 1136-1139 (2013)
    Abstract:
    Hydrophosphination of secondary propargylic alcohols generates phosphine-containing allylic alcohols that undergo facile [2,3]-sigmatropic rearrangements with chlorophosphines, furnishing highly enantioenriched, crystalline diphosphine monoxides. The configuration at the newly formed stereocenter is opposite to that expected based on prior studies, and an ab initio computational evaluation of the possible transition states was performed to help explain the stereochemical course of the reaction. © 2013 American Chemical Society.
  • Author:
    Wei X; Shu C; Haddad N; Zeng X; Patel N D; Tan Z; Liu J; Lee H; Shen S; Campbell S; Varsolona R J; Busacca C A; Hossain A; Yee N K; Senanayake C H
    Title:
    A highly convergent and efficient synthesis of a macrocyclic hepatitis C virus protease inhibitor BI 201302
    Source:
    Org Lett 15 (5), 1016-1019 (2013)
    Abstract:
    A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated SNAr reaction. © 2013 American Chemical Society.
  • Author:
    Busacca C A; Qu B; Farber E; Haddad N; Gret n; Saha A K; Eriksson M C; Wu J P; Fandrick K R; Han S; Grinberg N; Ma S; Lee H; Li Z; Spinelli M; Gold A; Wang G; Wipf P; Senanayake C H
    Title:
    Hydrophosphination of propargylic alcohols and amines with phosphine boranes
    Source:
    Org Lett 15 (5), 1132-1135 (2013)
    Abstract:
    The first uncatalyzed hydrophosphinations of propargylic amines and alcohols with phosphine- borane complexes are described. The reactions proceed at ambient temperature or below without the use of protecting groups or the need to handle pyrophoric secondary phosphines, furnishing air-stable phosphineborane-amines and alcohols in good yields. Utilization of chiral propargylic substrates and unsymmetrical secondary phosphineboranes leads to diastereomeric P-chiral products that can be separated by fractional crystallization or chromatography. Initial applications of these new P-X species to asymmetric catalysis are detailed. © 2013 American Chemical Society.
  • Author:
    Frese C K; Zhou H; Taus T; Altelaar A F M; Mechtler K; Heck A J R; Mohammed S
    Title:
    Unambiguous phosphosite localization using electron-transfer/higher-energy collision dissociation (EThcD)
    Source:
    J Proteome Res 12 (3), 1520-1525 (2013)
    Abstract:
    We recently introduced a novel scheme combining electron-transfer and higher-energy collision dissociation (termed EThcD), for improved peptide ion fragmentation and identification. We reasoned that phosphosite localization, one of the major hurdles in high-throughput phosphoproteomics, could also highly benefit from the generation of such EThcD spectra. Here, we systematically assessed the impact on phosphosite localization utilizing EThcD in comparison to methods employing either ETD or HCD, respectively, using a defined synthetic phosphopeptide mixture and also using a larger data set of Ti4+-IMAC enriched phosphopeptides from a tryptic human cell line digest. In combination with a modified version of phosphoRS, we observed that in the majority of cases EThcD generated richer and more confidently identified spectra, resulting in superior phosphosite localization scores. Our data demonstrates the distinctive potential of EThcD for PTM localization, also beyond protein phosphorylation. © 2013 American Chemical Society.
  • Author:
    Manosroi J; Lohcharoenkal W; Götz F; Werner R G; Manosroi W; Manosroi A
    Title:
    Transdermal absorption and stability enhancement of salmon calcitonin by Tat peptide
    Source:
    Drug Dev Ind Pharm 39 (4), 520-525 (2013)
    Abstract:
    Abstract Context: Highly organized structure of stratum corneum (SC) is the major barrier of the delivery of macromolecules such as proteins and peptides across the skin. Recently, cell penetrating peptides (CPPs) such as HIV1-trans-activating transcriptional (Tat) have been used to enhance the topical delivery of proteins and peptides. Objective: This study aimed to enhance the transdermal absorption and chemical stability of salmon calcitonin (sCT) by co-incubation with Tat. Materials and methods: Tat-sCT mixture at 1:1 molar ratio was prepared. Transdermal absorption and chemical stability of the mixture was evaluated in comparing with free sCT. Results: Tat-sCT mixture gave higher cumulative amounts and fluxes of sCT than free sCT. The maximum percentage of sCT of 58.36 ± 12.33% permeated into the receiving chamber was found in Tat-sCT mixture at 6 h which was 3.50 folds of free sCT. Tat-sCT mixture demonstrated better sCT stability than sCT solution after 1 month storage at 4°C, 25°C and 45°C. Discussion: The positively-charged arginine groups in Tat might be responsible for the binding of peptide complexes to negatively charged cell surfaces by electrostatic interactions and also the translocation of sCT through the excised skin. Conclusion: This study demonstrated the enhancements of transdermal absorption and stability of sCT by Tat peptide with potential for further application in transdermal delivery of other therapeutic peptides. © 2013 Informa Healthcare USA, Inc.
  • Author:
    Groselj U; Podiogar A; Novak A; Dahmann G; Golobic A; Stanovnik B; Svete J
    Title:
    Synthesis of tetrahydropyrazolo[1,5- C ]pyrimidine-2,7(1 H,3 H)-diones
    Source:
    Synthesis 45 (5), 639-650 SS-2012-Z0909-OP (2013)
    Abstract:
    A series of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3a-h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate (4). The synthesis comprises a four-step preparation of methyl N-Cbz-5-alkylamino-3- oxopentanoates 9a-c, their three-step transformation into 5-{2-[(alkyl) (benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a-c, three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl) amino]ethyl}pyrazolidin-3-ones 16b-h, followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3. Most of the synthetic steps were performed as a one-pot transformation. © Georg Thieme Verlag Stuttgart New York.
  • Author:
    Trost B M; Lam T M; Herbage M A
    Title:
    Regio-and enantioselective synthesis of pyrrolidines bearing a quaternary center by palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethanes
    Source:
    J Am Chem Soc 135 (7), 2459-2461 (2013)
    Abstract:
    Herein we describe the first use of disubstituted donors in the palladium-catalyzed trimethylenemethane (TMM) cycloaddition resulting in an enantioselective synthesis of highly substituted pyrrolidines. These cyanoalkyl donors 1 form all-carbon quaternary centers in a catalytic, asymmetric, and intermolecular manner uniquely using diamidophosphite ligands L2 and L3, generating synthetically important chiral building blocks in good yields and selectivities. © 2013 American Chemical Society.
  • Author:
    Han Z S; Goyal N; Herbage M A; Sieber J D; Qu B; Xu Y; Li Z; Reeves J T; Desrosiers J N; Ma S; Grinberg N; Lee H; Mangunuru H P R; Zhang Y; Krishnamurthy D; Lu B Z; Song J J; Wang G; Senanayake C H
    Title:
    Efficient asymmetric synthesis of P -chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents
    Source:
    J Am Chem Soc 135 (7), 2474-2477 (2013)
    Abstract:
    A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions. © 2013 American Chemical Society.
  • Author:
    Chambers D; Guo G; Kleintop B; Rasmussen H; Deegan S; Nowak S; Patterson K; Spicuzza J; Szulc M; Tombaugh K; Trone M D; Yuabova Z
    Title:
    Gmps for method validation in early development
    Source:
    Pharm Technol North Am 36 (7), 76-84 (2012)
    Abstract:
    no Abstract available
  • Author:
    Zhao Q; Li C; Senanayake C H; Tang W
    Title:
    Genetic and Pharmacological Modifications of Thrombin Formation in Apolipoprotein E-deficient Mice Determine Atherosclerosis Severity and Atherothrombosis Onset in a Neutrophil-Dependent Manner
    Source:
    Chemistry (Weinheim) 19 (7), 2261-2265 (2013)
    Abstract:
    Background: Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination. Methodology/Principal Findings: We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin (FII-/WT:ApoE-/-) was remarkably effective in limiting disease compared to control ApoE-/- mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in TMPro/Pro:ApoE-/- mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC), counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic TMPro/Pro:ApoE-/- mice. Conclusions/Significance: We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding the onset and progression of cardiovascular disease. © 2013 Borissoff et al.
  • Author:
    Bibee K P; Augustin R; Gazit V; Moley K H
    Title:
    The apical sorting signal for human GLUT9b resides in the N-terminus
    Source:
    Mol Cell Biochem, 1-11 Article in Press (2013)
    Abstract:
    The two splice variants of human glucose transporter 9 (hGLUT9) are targeted to different polarized membranes. hGLUT9a traffics to the basolateral membrane, whereas hGLUT9b traffics to the apical region. This study examines the sorting mechanism of these variants, which differ only in their N-terminal domain. Mutating a di-leucine motif unique to GLUT9a did not affect targeting. Chimeric proteins were made using GLUT1, a basolaterally targeted transporter, and GLUT3, an apically targeted protein whose signal lies in the C-terminus. Overexpression of the chimeric proteins in polarized cells demonstrates that the N-terminus of hGLUT9b contains a signal capable of redirecting GLUT1 to the apical membrane. The N-terminus of hGLUT9a, however, does not contain a basolateral signal sufficient enough to redirect GLUT3. Portions of the GLUT9a N-terminus were substituted with corresponding portions of the GLUT9b N-terminus to determine the motif responsible for apical targeting. The first 16 amino acids were not found to be a sufficient apical signal. The last ten amino acids of the N-termini differ only in amino-acid class at one location. In the B-form, leucine, a hydrophobic residue, is substituted for lysine, a basic residue, found in the A-form. However, mutation of the leucine in hGLUT9b to a lysine resulted in retention of the apical signal. We therefore believe the apical signal exists as an interplay between the final ten amino acids of the N-terminus and another motif within the protein such as the intracellular loop or other motifs within the N-terminus. © 2013 Springer Science+Business Media New York.
  • Author:
    Poulsen M H; Lucas S; Bach T B; Barslund A F; Wenzler C; Jensen C B; Kistensen A S; Stromgaard K
    Title:
    Structure-activity relationship studies of argiotoxins: Selective and potent inhibitors of ionotropic glutamate receptors
    Source:
    J Med Chem 56 (3), 1171-1181 (2013)
    Abstract:
    Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors. © 2013 American Chemical Society.
  • Author:
    MacDonald M J; Hesp C R; Schipper D J; Pesant M; Beauchemin A M
    Title:
    Highly enantioselective intermolecular hydroamination of allylic amines with chiral aldehydes as tethering catalysts
    Source:
    Chemistry (Weinheim) 19 (8), 2597-2601 (2013)
    Abstract:
    Chirally LinkedIn: Chiral aldehydes are effective tethering catalysts for enantioselective intermolecular hydroamination, which provides access to vicinal diamine motifs in good yields and excellent enantioselectivities (see scheme). This work highlights simple chiral ?-oxygenated aldehydes as effective organocatalysts capable of efficiently inducing asymmetry through transient intramolecularity. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
  • Author:
    Dziedzic, J; Fox, S. J.; Fox, T.; Tautermann, C.S.; Skylaris, C.-K.
    Title:
    Large-scale DFT calculations in implicit solvent - A case study on the T4 lysozyme L99A/M102Q protein
    Source:
    Int J Quantum Chem 113 (6), 771-785 (2013)
    Abstract:
    Recently, variants of implicit solvation models for first principles electronic structure calculations based on a direct solution of the nonhomogeneous Poisson equation in real space have been developed. These implicit solvation models are very elegant from a physical point of view as the solute cavity is defined directly via isosurfaces of the electronic density, and the molecular charge is polarized self-consistently by the reaction field of the dielectric continuum which surrounds the solute. Nevertheless, the implementation of these models is technically complex and requires great care. A certain level of care is required from users of such models as a number of numerical parameters need to be given appropriate values to obtain the most accurate and physically relevant results. Here, we describe in what parts of the solvent model each of these numerical parameters is involved and present a detailed study of how they can affect the calculation, using the solvation model which has been implemented in the ONETEP program for linear-scaling density functional theory (DFT) calculations. As ONETEP is capable of DFT calculations with thousands of atoms, we focus our investigation of the numerical parameters with a case study on protein-ligand complexes of the entire 2602-atom T4 Lysozyme L99/M102Q protein. We examine effects on solvation energies and binding energies, which are critical quantities for computational drug optimization and other types of biomolecular simulations. We propose optimal choices of these parameters suitable for routine "production" calculations. © 2012 Wiley Periodicals, Inc.
  • Author:
    Schultes S; Nijmeijer S; Engelhardt H; Kooistra AJ; Vischer HF; de Esch IJP; Haaksma EEJ; Leurs R; De Graaf C
    Title:
    Mapping histamine H4 receptor ligand binding modes.
    Source:
    MedChemComm 4 (1), 193-204 (2013)
  • Author:
    Grinberg N; Albu F; Fandrick K; Iorgulescu E; Medvedovici A
    Title:
    Assay at low ppm level of dimethyl sulfate in starting materials for API synthesis using derivatization in ionic liquid media and LC-MS.
    Source:
    J Pharm Biomed Anal 75, 1-6 (2013)
    Abstract:
    Dimethyl sulfate (DMS) is frequently used in pharmaceutical manufacturing processes as an alkylating agent. Trace levels of DMS in drug substances should be carefully monitored since the compound can become an impurity which is genotoxic in nature. Derivatization of DMS with dibenzazepine leads to formation of the N-methyl derivative, which can be retained on a reversed phase column and subsequently separated from other potential impurities. Such derivatization occurs relatively slowly. However, it can be substantially speed up if ionic liquids are used as reaction media. In this paper we report the use of 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (IL1) and 1-butyl-4-methylpyridinium tetrafluoroborate (IL2) as reaction media for the derivatization of DMS with dibenzazepine. It was determined that the stoichiometry between the substrate and DMS may be 1:1 or 2:1, in relation with the nature of the reaction media. An (+)ESI-MS/MS approach was used for quantitation of the derivatized product. Alternatively, DMS derivatization may be carried out with pyridine in acetonitrile (ACN). The N-methylpyridinium derivative was separated by hydrophilic interaction liquid chromatography (HILIC) and detected through (+)ESI-MS (in the SIM mode). In both cases, a limit of quantitation (LOQ) of 0.05 µg/ml DMS was achievable, with a linearity range up to 10 µg/ml. Both analytical alternatives were applied to assay DMS in 4-(2-methoxyethyl)phenol, which is used as a starting material in the synthesis of metoprolol. © 2012 Elsevier B.V.
  • Author:
    Wellenzohn B; Lessel U; Beller A; Isambert T; Hoenke C; Nosse B
    Title:
    Identification of new potent GFR119 agonists by combining virtual screening and combinatorial chemistry
    Source:
    J Med Chem 55 (24), 11031-11041 (2012)
    Abstract:
    Virtual screening in a huge collection of virtual combinatorial libraries has led to the identification of two new structural classes of GPR119 agonists with submicromolar in vitro potencies. Herein, we describe the virtual screening process involving feature trees fragment space searches followed by a 3D postprocessing step. The in silico findings were then filtered and prioritized, and finally, combinatorial libraries of target molecules were synthesized. Furthermore the so-called "activity-anchor principle" is introduced as an element to increase the chance to generate true hits. An activity anchor is a structural element expected to provide key contributions to a certain biological activity. Application of this technique has led to the discovery of two new GPR119-agonist hit series, one of which was further optimized to progress as a novel lead class. © 2012 American Chemical Society.
  • Author:
    Schultes S; Engelhardt H; Roumen L; Zuiderveld OP; Haaksma EEJ; deEsch IJP; Leurs R; deGraaf C
    Title:
    Combining quantum mechanical ligand conformation analysis and protein modeling to elucidate GPCR-ligand binding modes.
    Source:
    ChemMedChem 8 (1), 49-53 (2013)
    Abstract:
    no abstract available
  • Author:
    Rinker S; Barandun LJ; Diederich F; Kraemer O; Steffen A; van Gunsteren WF
    Title:
    Free enthalpies of replacing water modules in protein binding pockets.
    Source:
    J Comput Aided Mol Des 26 (12), 1293-309 (2012)
  • Author:
    Sedykh A; Fourches D; Duan J; Hucke O; Garneau M; Zhu H; Bonneau P; Tropsha A
    Title:
    Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake. Efflux and interactions.
    Source:
    Pharm Res, 1-12 (2012)
  • Author:
    Dach R; Song JJ; Roschangar F; Samstag W; Senanayake CH
    Title:
    The eight criteria defining a good chemical manufacturing process.
    Source:
    Org Process Res Dev 16 (11), 1697-1706 (2012)
  • Author:
    Bieler M; Koeppen H
    Title:
    The role of chemogenomics in the pharmaceutical industry.
    Source:
    Drug Dev Res 73 (7), 357-364 (2012)
    Abstract:
    Preclinical Research The goal of chemogenomics is the exploration of all possible interactions between compounds from the chemical space and targets from the biological space. This huge interaction matrix is only sparsely filled with experimental data but can be complemented by predicted values for selected ligand-target pairs. The prediction by computational chemogenomics uses the similarity principle that states that similar compounds have similar properties and that targets with similar binding sites bind similar ligands. Chemogenomics has a number of interesting applications, e.g. the prediction of the bioprofile of drugs including an assessment of possible adverse drug effects or the support of phenotypic screening by target fishing. This review focuses on applications of computational chemogenomics in pharmaceutical research and on the role that it plays in an industrial environment. © 2012 Wiley Periodicals, Inc.
  • Author:
    Chambers D; Guo G; Kleintop B; Rasmussen H; Deegan S; Nowak S; Patterson K; Spicuzza J; Szulc M; Tombaugh K; Trone MD; Yuabova Z
    Title:
    Gmps for methods validation in early development.
    Source:
    Pharm Technol North Am 36 (7), 76-84 (2012)
  • Author:
    Coutant M; Ge Z; McElvain JS; Miller SA; O'Connor D; Swanek F; Szulk M; Trone MD; Wong-Moon K; Yazdanian M; Yehl P; Zhang S
    Title:
    Early development gmps for small-molecule specifications.
    Source:
    Pharm Technol North Am 36 (10), 86-94 (2012)
    Abstract:
    a Analytical Research and Development, Pfizer Inc, Groton, CT, United States b Analytical Chemistry, Merck and Co. Inc, Rahway, NJ, United States Analytical and QC, Kythera Biopharmaceuticals, Calabasas, CA, United States d Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, NJ, United States e Analytical Development, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, United States Analytical Development, Biogen Idec, Cambridge, MA, United States g Analytical Development-Small Molecule, Millennium Pharmaceuticals, Inc, Cambridge, MA, United States h Analytical Research and Development, Amgen Inc, Thousand Oaks, CA, United States 1Pharnnaceutical Development, Teva Global Branded Products R and D, West Chester, PA, United States j Small Molecule Analytical Chemistry and Quality Control at Genentech, South San Francisco, CA, United States Global Pharmaceutical R and D, Abbott Laboratories, North Chicago, IL, United States
  • Author:
    Wagner M; Reiche K; Blume A; Garidel P
    Title:
    The electrokinetic potential of therapeutic proteins and its modulation: Impact on protein stability.
    Source:
    Colloids Surf (A) 415, 421-430 (2012)
    Abstract:
    Colloidal protein stability in solution is governed by protein-protein interactions as well as by interactions with surrounding molecules (e.g. excipients, buffer and satt components, solvent molecules) and environmental conditions such as temperature. Also, the thermodynamic stability of a protein has an impact on the overall colloidal stability of protein in an aqueous environment. Electrostatic interactions between proteins have been described to be of high relevance for colloidal stability, for example the formation of protein particles. One parameter for the evaluation of such interactions in solution is the electrophoretic mobility from which the electrokinetic potential (EP) (also known as the zeta potential, ZP) is obtained. The electrokinetic potential, respective EP, refers to the potential at the shear surface where the protein molecules with their associated sheath of counter-ions and excipients slip through the solution, which is under the influence of an applied external electrical field. The current study investigated the electrokinetic potential of therapeutic proteins and how and to what extent the electrokinetic potential can be influenced by variations of solution conditions (e.g. pH, salts and buffer components, amino acids, carbohydrates or detergents). The interactions of proteins, such as monoclonal antibodies, with different excipients are discussed in terms of the DLVO theory and colloidal stability, respectively.Furthermore, the electrokinetic potential is used for the determination of the isoelectric point of several proteins and compared to theoretical values derived from the total net charge based on the primary amino acid sequence.ln addition, we investigated to what extent the electrokinetic potential of proteins can be modulated by solution conditions and whether the electrokinetic potential of various proteins in different solution conditions correlate with experimental derived colloidal and thermal stability. © 2012 Elsevier B.V.
  • Author:
    Moss N; Xiong Z; Burke M; Cogan D; Gao DA; Haverty K; Heim-Riether A; Hickey ER; Nagaraja R; Netherton M; O'Shea K; Ramsden P; Schwartz R; Shih D-T; Ward Y; Young E; Zhang Q
    Title:
    Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement.
    Source:
    Bioorg Med Chem Lett 22 (23), 7189-7193 (2012)
  • Author:
    Luner PE; Zhang Y; Abramov YA; Carvajal MT
    Title:
    Evaluation of milling method on the surface energetics of molecular crystals using inverse gas chromatography.
    Source:
    Crystal Growth Des 12 (11), 5271-5282 (2012)
  • Author:
    Davy JA; Mason JW; Moreau B; Wulff JE
    Title:
    Xanthates as synthetic equivalents of oxyacyl radicals: Access to lactones under tin-free conditions.
    Source:
    J Org Chem 77 (14), 6332-6339 (2012)
    Abstract:
    In addition to their utility in Barton-McCombie deoxygenations, xanthates can engage in 5-exo-trig radical cyclizations to afford lactones after oxidative workup. In this paper, we describe a tin-free protocol that provides direct access to lactones via hydrolysis of labile thioketal intermediates. Analysis of several systems of varying complexity reveals that the reaction is most applicable for constrained systems in which the reacting center is prepositioned near the radical-accepting alkene
  • Author:
    Tremblay M; Bonneau P; Bousquet Y; DeRoy P; Duan J; Duplessis M; Gagnon A; Garneau M; goudeau N; Guse I; Hucke O; Kawai S H; Lemke C T; Mason S W; Simoneau B; Surprenant S; Titolo S; Yoakim C
    Title:
    Inhibition of HIV-1 capsid assembly: Optimization of the antiviral potency by site selective modifications at N1, C2 and C16 of a 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole scaffold
    Source:
    Bioorg Med Chem Lett 22 (24), 7512-7517 (2012)
    Abstract:
    A uHTS campaign led to the discovery of a 5-(5-furan-2-ylpyrazol-1-yl)-1H-benzimidazole series that inhibits assembly of HIV-1 capsid. Synthetic manipulations at N1, C2 and C16 positions improved the antiviral potency by a . The X-ray structure of 33 complexed with the capsid N-terminal domain allowed identification of major interactions between the inhibitor and the protein. © 2012 Elsevier Ltd. All rights reserved.
  • Author:
    Beckers T; Mahboobi S; Sellmer A; Winkler M; Eichhorn E; Pongratz H; Maier T; Ciossek T; Baer T; Kelter G; Fiebig H-H; Schmidt M
    Title:
    Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases.
    Source:
    MedChemComm 3 (7), 829-835 (2012)
    Abstract:
    The regulation of chromatin structure and, therefore, transcriptional activity of histone proteins by reversible lysine acetylation is an important posttranslational modification. Inhibitors of histone deacetylase (HDAC) are considered as promising new anti-neoplastic drugs. The hydroxamic acid SAHA e.g. is currently used in the treatment of advanced primary cutaneous T-cell lymphoma. The EGFR protein tyrosine kinase inhibitor erlotinib is a prominent drug in cancer chemotherapy and currently approved for treatment of non-small cell lung cancer. In this report, we present a novel strategy for cancer drug development by a combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining two distinct pharmacological properties in one molecule, we expect a broader activity spectrum and less likelihood of drug resistance in cancer patients. The combination led to substances with both HDAC inhibitory properties and EGFR as well as HER2 kinase inhibitory activities. © The Royal Society of Chemistry 2012.
  • Author:
    Bonderoff SA; West FG; Tremblay M
    Title:
    Superacid-catalyzed friedel-crafts cyclization of unactivated alkenes.
    Source:
    Tetrahedron Lett 53 (34), 4600-4603 (2012)
    Abstract:
    Trifluoromethanesulfonimide is an effective catalyst for Friedel-Crafts cyclizations of simple, nonpolarized alkenes with a variety of pendant arenes. A catalyst loading of 0.5 - 1.0 mol % effects clean cyclization to form 5- to 7-membered carbocycles with generally short reaction times and good to excellent yields under reflux or microwave heating. © 2012 Elsevier Ltd. All rights reserved.
  • Author:
    Gapsys V; Seeliger D; De Groot BL
    Title:
    New soft-core potential function for molecular dynamics based alchemical free energie calculations.
    Source:
    J Chem Theor Comput 8 (7), 2373-2382 (2012)
    Abstract:
    The fields of rational drug design and protein engineering benefit from accurate free energy calculations based on molecular dynamics simulations. A thermodynamic integration scheme is often used to calculate changes in the free energy of a system by integrating the change of the systems Hamiltonian with respect to a coupling parameter. These methods exploit nonphysical pathways over thermodynamic cycles involving particle introduction and annihilation. Such alchemical transitions require the modification of the classical nonbonded potential energy terms by applying soft-core potential functions to avoid singularity points. In this work, we propose a novel formulation for a soft-core potential to be applied in nonequilibrium free energy calculations that alleviates singularities, numerical instabilities, and additional minima in the potential energy for all combinations of nonbonded interactions at all intermediate alchemical states. The method was validated by application to (a) the free energy calculations of a closed thermodynamic cycle, (b) the mutation influence on protein thermostability, (c) calculations of small ligand solvation free energies, and (d) the estimation of binding free energies of trypsin inhibitors. The results show that the novel soft-core function provides a robust and accurate general purpose solution to alchemical free energy calculations. © 2012 American Chemical Society.
  • Author:
    Fandrick DR; Roschangar F; Kim C; Hahm BJ; Cha MH; Kim HY; Yoo G; Kim T; Reeves JT; Song JJ; Tan Z; Qu B; Haddad N; Shen S; Grinberg N; Lee H; Yee N; Senanayake CH
    Title:
    Preparative synthesis via continuous flow of 4,4,5,5-tetramethyl-2-(3- trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane: A general propagylation reagent.
    Source:
    Org Process Res Dev 16 (5), 1131-1140 (2012)
    Abstract:
    A scalable process for the preparation of 4,4,5,5-tetramethyl-2-(3- trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane from trimethylsilylpropyne, isopropyl pinacol borate, and n-butyllithium is described. Problems associated with implementing a typical aqueous workup and batch process into production due to borolane "ate" equilibration and protonolysis are presented. To address these issues, a continuous-flow and distillation process was developed which efficiently produced 297 kg of the key propargylation reagent
  • Author:
    Li W; Gao JJ; Lorenz JC; Xu J; Johnson J; Ma S; Lee H; Grinberg N; Busacca CA; Lu B; Senanayake CH
    Title:
    Process development and pilot-plant synthesis of (S)-tert-butyl 1-oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the scale-up of Kulinkovich-Szymoniak cyclopropanation.
    Source:
    Org Process Res Dev 16 (5), 336-339 (2012)
    Abstract:
    A practical and scalable synthesis of (S)-tert-butyl 1-oxo-1-(1-(pyridin-2- yl)cyclopropylamino)propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starting from readily available materials. A modified Kulinkovich-Szymoniak cyclopropanation of a nitrile followed by in situ amide formation with an activated carboxylic acid derivative afforded the target product in about 50% overall isolated yield and >97% purity.
  • Author:
    Li Y; Xu J; Lai WG; Whitcher-Johnstone A; Tweedie DJ
    Title:
    Metabolic switching of BILR 355 in the presence of ritonavir. II. Uncovering novel contributions by gut bacteria and aldehyde oxidase
    Source:
    Drug Metab Dispos 40 (6), 1130-1137 (2012)
    Abstract:
    Ritonavir (RTV) was used as a boosting agent to increase the clinical exposure of 11-ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl) oxy]ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355), an inhibitor of the human immunodeficiency virus, by inhibiting the CYP3A-mediated metabolism of BILR 355. However, although the levels of BILR 355 increased upon concomitant administration of RTV, a metabolite of BILR 355, BILR 516, which was not detected previously in humans dosed with BILR 355 alone, became a disproportionate human metabolite with levels exceeding the parent levels at steady state. This was an unusual finding based on the in vitro and in vivo metabolic profiles of BILR 355 available at that time. Our studies reveal that BILR 355 is reduced to an intermediate, BILR 402, by gut bacteria and the reduced metabolite (BILR 402) is then oxidized by aldehyde oxidase to form BILR 516, the disproportionate human metabolite. The role of aldehyde oxidase helped to explain the somewhat unique formation of BILR 516 in humans compared with preclinical animal species. This article underlines the increasing importance of two individually atypical enzymes in drug development, gut bacterial biotransformation and aldehyde oxidase, which in combination provided a unique metabolic pathway. In addition, this article clearly elucidates an example of novel metabolic switching and, it is hoped, raises awareness of the potential for metabolic switching in combination drug therapies
  • Author:
    Li Y; Lai WG; Whitcher-Johnstone A; Busacca CA C; Eriksson MC; Lorenz JC; Tweedie DJ
    Title:
    Metabolic switching of BILR 355 in the presence of ritonavir. I. Identifying an unexpected disproportionate human metabolite.
    Source:
    Drug Metab Dispos 40 (6), 1122-1129 (2012)
    Abstract:
    11-Ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy] ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355) is an inhibitor of the human immunodeficiency virus-1. BILR 355 exhibited a nonlinear pharmacokinetic profile and low exposure after oral administration to humans. This article describes the in vitro metabolism of BILR 355, which is correlated with the in vivo nonlinearity findings. Our in vitro studies had demonstrated that BILR 355 was extensively metabolized by cytochrome P450 3A. Thus, BILR 355 was concomitantly administered with ritonavir (RTV) in an attempt to boost systemic exposure, which did occur in humans. In addition, the expectation was that the overall metabolism of BILR 355 would be decreased with concomitant administration of RTV. Subsequent metabolite profiling was performed using human plasma samples obtained from clinical phase Ib studies with concomitant administration of BILR 355 and RTV. A total of 18 metabolites was observed. Their structures were proposed on the basis of high-performance liquid chromatography-tandem mass spectrometry technologies, and 10 metabolites were confirmed by comparison with synthetic standards. We were surprised to find that a disproportionate human metabolite, BILR 516, was uncovered during this metabolite profiling study and pharmacokinetic analysis of BILR 516 showed that it had a longer half-life and higher exposure than the parent compound at steady state. Of interest, BILR 516 was not detected in human plasma when BILR 355 was administered alone. Therefore, whereas RTV boosted the exposure of BILR 355, it resulted in a significant metabolic switching of BILR 355. Overall, this article demonstrates an unusual example of metabolic switching and raises concern about the consequence of metabolic switching during drug development. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics. Reaxys Database Information
  • Author:
    Girard T; El-Far M; Gaucher D; Acuto O; Beaule G; Michel F; Mourad W; Sekaly R-P
    Title:
    A conserved polylysine motif in CD86 cytoplasmic tail is necessary for cytoskeletal association and efective costimulation.
    Source:
    Biochem Biophys Res Commun 423 (2), 301-307 (2012)
    Abstract:
    T cell activation requires both antigen specific and co-stimulatory signals that include the interaction of CD28 with its ligands CD80 and CD86. These signals are delivered by antigen presenting cells (APC) in the context of the immunological synapse (IS). Reorganization of the cytoskeleton is required for the formation and maintenance of the IS. Our results show that a highly conserved polylysine motif in CD86 cytoplasmic tail, herein referred to as the K4 motif, is responsible for the constitutive association of CD86 to the cytoskeleton in primary human APC as well as in a murine APC model. This motif is not involved in initial APC:T cell conjugate formation but mutation of the K4 motif affects CD86 reorientation at the IS. Importantly, APCs expressing CD86 with mutated K4 motif are severely compromised in their capacity to trigger complete T cell activation upon peptide presentation as measured by IL-2 secretion. Altogether, our results reveal the critical importance of the cytoskeleton-dependent CD86 polarization to the IS and more specifically the K4 motif for effective co-signaling. © 2012 Elsevier Inc. Reaxys Database Information
  • Author:
    Engelhardt H; de Esch IJP; Kuhn D; Smits RA; Zuiderveld OP; Dobler J; Mayer M; Lips S; Arnhof H; Scham D; Haaksma EEJ; Leurs R
    Title:
    Detailed structure-activity relationship of indolecarboxamides as H 4 receptors ligands.
    Source:
    Eur J Med Chem Article in Press (2012)
  • Author:
    Wang X-J; Zhang L; Sun X; Lee H; Krishnamurthy D; O'Meara JA; Landry S; Yoakim C; Simoneau B; Yee NK; Senanayake CH
    Title:
    Practical synthesis of a benzophenone-based NNRT inhibitor of HIV-1.
    Source:
    Org Process Res Dev 16 (4), 561-566 (2012)
    Abstract:
    A convergent synthesis of NNRTI 1 is described. The key step involves a direct coupling of acid chloride 4 with Grignard reagent 11 in the presence of bis[2-(N,N-dimethylamino)ethyl] ether that moderates the reactivity of the Grignard reagent to give benzophenone 7. An efficient 2-step process for the preparation of 2-fluoro-3-methyl-4-aminobenzoic acid (3) is also described. © 2012 American Chemical Society.
  • Author:
    Davy JA; Moreau B; Wulff JE
    Title:
    Tandem dihydroxylation, hemiketalization and conjugate addition leading to a singly anomeric spiroketal.
    Source:
    Synthesis 44 (12), 1854-1862 (2012)
    Abstract:
    A novel, highly stereoselective tandem dihydroxylation, hemiketalization and conjugate addition reaction is reported that transforms a linear meso-functionalized bis-enone into a substituted singly anomeric spiroketal, effectively controlling six stereocenters in a single operation. As part of an effort to explore the thermodynamic consequences of establishing the singly anomeric spiroketal in this system, the assembly of a related fully anomeric spiroketal possessing an unusual ketal-spiroketal-ketal framework is demonstrated. © 2012 Elsevier B.V. All rights reserved. Reaxys Database Information
  • Author:
    Baškovc J; Dahmann G; Golobic A; Grošelj U; Kocar D; Stanovnik B; Svete J
    Title:
    Diversity-oriented synthesis of 1-substituted 4-aryl-6-oxo-1,6- dihydropyridine-3-carboxamides. Diversity-oriented synthesis of 1-substituted 4-aryl-6-oxo-1,6- dihydropyridine-3-carboxamides.
    Source:
    QSAR Comb Sci 14 (9), 513-519 (2012)
    Abstract:
    A simple five-step diversity-oriented synthesis of 1-substituted 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxamides was developed. Treatment of dimethyl 2-((dimethylamino)methylidene)-3-oxopentanedioate with twenty primary amines gave 1-substituted methyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3- carboxylates. Transformation into the corresponding 4-tosyloxy and 4-chloro derivatives, followed by Suzuki-Miyaura arylations gave a series of eleven N-substituted methyl 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxylates. Combinatorial screening was employed to establish suitable reaction conditions for Suzuki-Miyaura arylation of N-alkylpyridones. Hydrolysis of the esters followed by parallel solution-phase amidation of the corresponding carboxylic acids with primary and secondary amines furnished a library of seventeen final products. © 2012 American Chemical Society.
  • Author:
    Hill D W; Baveghems C L; Albaugh D R; Kormos T M; Lai S; Ng H K; Grant D F
    Title:
    Correlation of Ecom 50 values between mass spectrometers: Effect of collision cell radiofrequency voltage on calculated survival yield
    Source:
    Rapid Commun Mass Spectrom 25 (19), 2303-2310 (2012)
    Abstract:
    Ratione: The determination of the center-of-mass energy at which 50% of a precursor ion decomposes (Ecom 50) during collision-induced dissociation (CID) is dependent on the chemical structure of the ion as well as the physical and electrical characteristics of the collision cell. The current study was designed to identify variables influencing Ecom 50 values measured on four different mass spectrometers. Methods: Fifteen test compounds were protonated using + ve electrospray ionization and the resulting ions were fragmented across a range of collision energies by CID. Survival yield versus collision energy curves were then used to calculate Ecom 50 values for each of these [M+H] + ions on four different mass spectrometers. In addition, the relative recovery of the [M+H] + ions of eight compounds ranging in molecular weight from 46 to 854 Da were determined at collision cell radiofrequency (RF) voltages ranging from 0 to 600 V. RESULTS: Ecom 50 values determined on the four instruments were highly correlated (r 2 values ranged from 0.953 to 0.992). Although these overall correlations were high, we found different maximum ion recoveries depending on collision cell RF voltage. High-mass ions had greater recovery at higher collision cell RF voltages, whereas low-mass ions had greater recovery at lower collision cell RF voltages as well as a broader range of ion recoveries. CONCLUSIONS: Ecom 50 values measured on four different instruments correlated surprisingly well given the differences in electrical and physical characteristics of the collision cells. However, our results suggest caution when comparing Ecom 50 values or CID spectra between instruments without correcting for the effects of RF voltage on ion transfer efficiency. Copyright © 2012 John Wiley &amp; Sons, Ltd.
  • Author:
    Tang W; Patel ND; Xu G; Xu X; Savoie J; Ma S; Hao M-H; Keshipeddy S; Capacci AG; Wei X; Zhang Y; Gao JJ; Li W; Rodriguez S; Lu BZ; Yee NK; Senanayake CH
    Title:
    Efficient chiral monophosphorus ligands for asymmetric Suzuki-Miyaura coupling reactions
    Source:
    Org Lett 14 (9), 2258-2261 (2012)
    Abstract:
    A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a pi-pi interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction. © 2012 American Chemical Society.
  • Author:
    Zimniak T; Fitz V; Zhou H; Lampert F; Opravil S; Mechtler K; Stolt-Bergner P; Westermann S
    Title:
    Spatiotemporal regulation of the lpl1/aurora activity by direct Cdk1 phosphorylation.
    Source:
    Curr Biol 22 (9), 787-793 (2012)
  • Author:
    Beck B
    Title:
    BioProfile - Extract knowledge from corporate databases to assess cross-reactivities of compounds.
    Source:
    Bioorg Med Chem 20 (18), 5428-5435 (2012)
    Abstract:
    In the last 10-15 years, many new technologies and approaches have been implemented in research in the pharmaceutical industry; these include high-throughput screening or combinatorial chemistry, which result in a rapidly growing amount of biological assay and structural data in the corporate databases. Efficient use of the data from this growing data mountain is a key success factor; 'provide as much knowledge as possible as early as possible and therefore enable research teams to make the best possible decision whenever this decision can be supported by stored data'. Here, an approach which started several years ago to obtain as much information as possible out of historical assay data stored in the corporate database is described. It will be shown how important a careful preprocessing of the stored data is to enhance its information. Different possibilities for accessing and to analyzing the preconditioned data are in place. Some of will be described in the examples. © 2011 Elsevier Ltd. All rights reserved.
  • Author:
    Gnamm C; Jeanguenat A; Datton A C; Grimm C; Kloer D P; Crossthwaite A J
    Title:
    Novel diamide insecticides: Sulfoximines, sulfonimidamides and other new sulfonimidoyl derivatives.
    Source:
    Bioorg Med Chem Lett 22 (11), 3800-3806 (2012)
    Abstract:
    Novel insecticidal anthranilamides with elaborated sulfur-containing groups are described. The synthesis of compounds with functional groups such as sulfoximines and scarcely reported groups such as sulfonimidoyl hydrazides and hydroxylamides, their in vitro and in vivo biological activity as well as their physical properties are reported. © 2012 Elsevier Ltd. All rights reserved.
  • Author:
    Crcek B; Baskovc J; Groselj U; Kocar D; Dahmann G; Stanovnik B; Svete J
    Title:
    Parallel synthesis of 2-substituted 6-(5-Oxo-1-phenylpyrrolidin-3yl) pyrimidine-5-carboxamides.
    Source:
    Molecules 17 (5), 5363-5384 (2012)
    Abstract:
    A library of 24 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10{1,2; 1-12} was prepared by a parallel solution-phase approach. The synthesiscomprises a five-step transformation of itaconic acid (11) into 1-methyl and 1-phenyl substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic acids 17{1,2} followed by parallel amidation of 17{1,2} with a series of 12 aliphatic amines 18{1-12} to afford the corresponding carboxamides 10 in good overall yields and in 80-100% purity. © 2012 by the Authors. -------------------------------------------------------------------------- ------ Reaxys Database Information |
  • Author:
    Cozma A; Vlase L; Ignat A; Zaharia V; Gocan S; Grinberg N
    Title:
    Prediction of the lipophilicity of eight new p-toluenesulfonyl-hydrazinothiazole and hydrazine-bis-thiazole derivates: A comparison between RP-HPTLC and RP-HPLC.
    Source:
    J Liq Chromatogr Relat Technol 35 (4), 590-601 (2012)
  • Author:
    Frischmuth A; Unsinn A; Groll K; Stadtmüller H; Knochel P
    Title:
    Preparations and reactions of SF 5-substituted aryl and heteroaryl derivatives via Mg and Zn organometallics
    Source:
    Chemistry (Weinheim) 18 (33), 10234-10238 (2012)
    Abstract:
    Polyfunctional SF 5-substituted cycles: Several organometallic sequences using zinc, copper, and magnesium intermediates were developed to prepare a broad range of SF 5-substituted aromatic and heterocyclic compounds of potential interest for pharmaceutical applications. Copyright © 2012 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.
  • Author:
    Hampel T; Neubauer T; Van Leeuwen T; Bach T
    Title:
    Stereoselective preparation of (E)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: Convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its C7 epimer
    Source:
    chemistry (Weinheim) 18 (33), 10382-10392 (2012)
    Abstract:
    The title compounds were synthesized in a longest sequence of 27 linear steps and with an overall yield of 2.9 and 3.9 %. In the course of the synthesis, two aldehydes representing carbon fragments C1-C7 (Eastern fragment) and C9-C21 (Western fragment) were prepared from D-mannitol, each of which incorporated a key stereogenic center at the respective secondary methyl ether group (C6, C12) from the chiral pool material. The assembly of the two aldehydes was achieved employing ?-chloroethyl magnesium chloride as a two-carbon building block. The carbenoid reagent was generated from ?-chloroethyl para-tolylsulfoxide by sulfoxide-magnesium exchange and it added smoothly to the highly sensitive aldehyde of the Eastern fragment (C1-C7). Upon oxidation, an ?-chloroethyl ketone was generated, which underwent a clean and high-yielding reductive SmI 2-promoted addition to the other aldehyde fragment. Dehydration delivered the key double bond between C8 and C9 in an overall yield of 72 % over four steps. The method was shown to be generally applicable to the racemization-free conversion of several aldehydes into the respective ?-chloroethyl ketone (11 examples, 64-95 %) and to the coupling protocol (5 examples, 66-90 %). The further course of the geldanamycin hydroquinone synthesis included a diastereoselective reduction at C7 and the implementation of the amino group at C20. Since deprotection of the two isopropyl protecting groups could not be achieved in significant yields, the structure of 18,21-diisopropyl-geldanamycin hydroquinone was proven by its independent synthesis from the natural product. Convergency in the synthesis of the geldanamycin skeleton has been achieved by employing a magnesium carbenoid as a two-carbon building block, connecting two aldehyde fragments in an efficient and high yielding manner. The preparation of ?-chloroethyl ketones from aldehydes has been investigated (11 examples, 64-95 % yield) and the title compounds have been prepared from advanced precursor 1. Copyright © 2012 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.
  • Author:
    Jacob S; Mendonsa SD
    Title:
    Strategies for the analysis of pharmaceutical cocrystals using HPLC with charged aerosol detection.
    Source:
    Chromatographia 75 (7-8), 321-328 (2012)
    Abstract:
    Several active pharmaceutical ingredients are currently being developed as pharmaceutical cocrystals as these systems often have superior properties compared to traditional pharmaceutical forms. Pharmaceutical cocrystal formers typically used are polar, small molecule acids or bases which often lack a UV chromophore. Their polar nature results in almost no reversed phase retention and their detection typically cannot be done with UV. Here we discuss approaches for the analysis of pharmaceutical cocrystals using HPLCcolumns designed for polar retention, ion pairing chromatography (IPC), and hydrophilic interaction chromatography (HILIC) using model cocrystal formers. Corona charged aerosol detection (CAD) was used to monitor the cocrystal formers. L-alanine was used as a model basic cocrystal former, and succinic acid and glutaric acid were used as model acidic cocrystal formers. The acidic cocrystal formers were adequately retained on a C18 column. Heptafluorobutyric acid was used as the ionpairing reagent for L-alanine as it was unretained without the ion-pairing reagent. HILIC, a newer approach for polar compound retention, was also investigated. Using the HILIC mode, all three model cocrystal formers were retained adequately. Of all the approaches studied for the analysis of the cocrystal formers, HILIC appears to be the best choice as the same column can be used for both acidic and basic cocrystal formers. With IPC, the ion-pairing reagent permanently alters the column chemistry and dedicated columns are required for each ion-pairing reagent used. CAD detection provided a linear response in the 80-100% test concentration range for the analytes studied here. © 2012 Springer-Verlag.
  • Author:
    Engelhardt H; De Esch I J P; Kuhn D; Smits R A; Zuiderveld O P; Dobler J; Mayer M; Lips S; Amhof H; Scham D; Haaksma E E J; Leurs R
    Title:
    Detailed structure-activity relationship of indolecarboxamides as H 4 receptor ligands
    Source:
    Eur J Med Chem 54, 660-668 (2012)
    Abstract:
    A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H 4R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47-55). In addition to the H 4-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H 4R protein. © 2012 Elsevier Masson SAS. All rights reserved.
  • Author:
    Neumann S; Bidon T; Branschädel M; Krippner Heidenreich A; Scheurich P; Doszczak M
    Title:
    The transmembrane domains of TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 co-regulate apoptotic signaling capacity
    Source:
    PloS ONE 7 (8) e42526 (2012)
    Abstract:
    TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) ligand family that exerts its apoptotic activity in human cells by binding to two transmembrane receptors, TRAILR1 and TRAILR2. In cells co-expressing both receptors the particular contribution of either protein to the overall cellular response is not well defined. Here we have investigated whether differences in the signaling capacities of TRAILR1 and TRAILR2 can be attributed to certain functional molecular subdomains. We generated and characterized various chimeric receptors comprising TRAIL receptor domains fused with parts from other members of the TNF death receptor family. This allowed us to compare the contribution of particular domains of the two TRAIL receptors to the overall apoptotic response and to identify elements that regulate apoptotic signaling. Our results show that the TRAIL receptor death domains are weak apoptosis inducers compared to those of CD95/Fas, because TRAILR-derived constructs containing the CD95/Fas death domain possessed strongly enhanced apoptotic capabilities. Importantly, major differences in the signaling strengths of the two TRAIL receptors were linked to their transmembrane domains in combination with the adjacent extracellular stalk regions. This was evident from receptor chimeras comprising the extracellular part of TNFR1 and the intracellular signaling part of CD95/Fas. Both receptor chimeras showed comparable ligand binding affinities and internalization kinetics. However, the respective TRAILR2-derived molecule more efficiently induced apoptosis. It also activated caspase-8 and caspase-3 more strongly and more quickly, albeit being expressed at lower levels. These results suggest that the transmembrane domains together with their adjacent stalk regions can play a major role in control of death receptor activation thereby contributing to cell type specific differences in TRAILR1 and TRAILR2 signaling. © 2012 Neumann et al.
  • Author:
    Lessel U; Wellenzohn B; Fischer JR; Rarey M
    Title:
    Design of combinatoral libaries for the exploration of virtual hils from fragment space searches with LoFT.
    Source:
    J Chem Inform Modeling 52 (2), 373-379 (2012)
  • Author:
    Wassermann A M; Haebel P; Weskamp N; Bajorath J
    Title:
    SAR matrices: Automated extraction of information-rich SAR tables from large compound data sets
    Source:
    J Chem Inform Modeling 52 (7), 1769-1776 (2012)
    Abstract:
    We introduce the SAR matrix data structure that is designed to elucidate SAR patterns produced by groups of structurally related active compounds, which are extracted from large data sets. SAR matrices are systematically generated and sorted on the basis of SAR information content. Matrix generation is computationally efficient and enables processing of large compound sets. The matrix format is reminiscent of SAR tables, and SAR patterns revealed by different categories of matrices are easily interpretable. The structural organization underlying matrix formation is more flexible than standard R-group decomposition schemes. Hence, the resulting matrices capture SAR information in a comprehensive manner. © 2012 American Chemical Society.
  • Author:
    Christ C D; Zentgraf M; Kriegl J M
    Title:
    Mining electronic laboratory notebooks: Analysis, retrosynthesis, and reaction based enumeration
    Source:
    J Chem Inform Modeling 52 (7), 1745-1756 (2012)
    Abstract:
    An approach to automatically analyze and use the knowledge contained in electronic laboratory notebooks (ELNs) has been developed. Reactions were reduced to their reactive center and converted to a string representation (SMIRKS) which formed the basis for reaction classification and in silico (retro-)synthesis. Of the SMIRKS that occurred at least five times, 98% successfully regenerated the original product. The extracted reaction rules (SMIRKS) and corresponding reactants span a virtual chemical space which showed a strong dependence on the size of the reactive center. Whereas relatively few robust reaction types were sufficient to describe a large part of all reactions, considerably more reaction rules were necessary to cover all reactions in the ELN. Furthermore, reaction sequences were extracted to identify frequent combinations and diversifying reaction steps. Based on the extracted knowledge a (retro-)synthesis tool was built allowing for de novo design of compounds which have a high chance of being synthetically accessible. In an example application of the de novo design tool, various feasible retrosynthetic routes to the query molecule were obtained. Reaction based enumeration along the top ranked route yielded a library of 29 920 compounds with diverse properties, 99.9% of which are novel in the sense that they are unknown to the public domain. © 2012 American Chemical Society.
  • Author:
    Elsayad K; Urich A; Nemethova M; Small JV; Unterrainer K; Heinze KG
    Title:
    Fluorescence enhancements and spectral modifications near the cut-off frequency of plasmonic structure.
  • Author:
    Lessel U; Wellenzohn B; Fischer J R; Rarey M
    Title:
    Design of Combinatorial Libraries for the Exploration of Virtual Hits from Fragment Space Searches with LoFT.
    Source:
    J Chem Inform Modeling 52 (2), 373-379 (2012)
    Abstract:
    A case study is presented illustrating the design of a focused CDK2 library. The scaffold of the library was detected by a feature trees search in a fragment space based on reactions from combinatorial chemistry. For the design the software LoFT (Library optimizer using Feature Trees) was used. The special feature called FTMatch was applied to restrict the parts of the queries where the reagents are permitted to match. This way a 3D scoring function could be simulated. Results were compared with alternative designs by GOLD docking and ROC S 3D alignments.
  • Author:
    Haberstock S; Roos C; Hoevels Y; Doetsch V; Schnapp G; Pautsch A; Bernhard F
    Title:
    A systematic approach to increase the efficiency of membrane protein production in cell-free exression systems.
    Source:
    Protein Express Purif 82 (2), 308-316 (2012)
  • Author:
    Roy A; Chanana G
    Title:
    Analytical and formulation attributes: In developing generic sterile injectable liquid and lyophilized drugs (part 1)
    Source:
    Chim Oggi 30 (1), 78-80 (2012)
  • Author:
    Andrews MJI; Andrew Clase J; Bar G; Tricarico G; Edwards PJ; Brys R; Chambers M; Schmidt W; MacLeod A; Hirst K; Allen V; Birault V; Le J; Harris J; Self A; Nash K; Dixon G
    Title:
    Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show actifity using in vitro and in vivo models of rheumatoid arthritis.
    Source:
    Bioorg Med Chem Lett 22 (6), 2266-2270 (2012)
  • Author:
    Qu B; Haddad N; Rodriguez S; Lee H; Ma S; Zeng X; Reeves DC; Sidhu KPS; Lorenz JC; Grinberg N; Busacca CA; Krishnamurthy D; Senanayake CH
    Title:
    Chelation controlled reductive amination of cyclic ketones to trans-4-methoxycyclohexylamines: 9-BBN reduction mediated with FeCl3.
    Source:
    Tetrahedron Lett 53 (15), 1982-1986 (2012)
    Abstract:
    A novel trans-diastereoselective reductive amination of 4-substituted cyclohexanones is described using 9-BBN as reducing agent in the presence of FeCl 3. The method permits efficient synthesis of structurally diverse 4-trans-alkoxycyclohexylamines. © 2011 Elsevier Inc. All rights reserved.
  • Author:
    Larson ET; Ojo KK; Murphy RC; Johnson SM; Zhang Z; Kim JE; Leibly DJ; Fox AMW; Reid MC; Dale EJ; Perera BGK; Kim J; Hewitt SN; Hol WGJ; Verlinde CLMJ; Fan E; van Voorhis WC; Maly DJ; Merrit EA
    Title:
    Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1.
    Source:
    J Med Chem 55 (6), 2803-2810 (2012)
    Abstract:
    Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC. © 2012 American Chemical Society.
  • Author:
    Timmerman P; Lausecker B; Barosso B; Van Amsterdam P; Luedtke S; Dijeksman J
    Title:
    Conference report:'Large meets small'. Connecting the bioanalytical community around peptide and protein bioanalysis with LC-MS/MS.
    Source:
    Bioanalysis 4 (6), 627-631 (2012)
  • Author:
    Dijksman J; Timmerman P; Abbott R; Barroso B; Kloeppel MB; Companjen A; Golob M; Gordon B; Herling C; Knutsson M; Luedtke S; Rasmussen BB; Stoellner D; Vieser E; Young G; Van Amsterdam P
    Title:
    Conference report: 'Less is More'. Defining modern bioanalysis.
    Source:
    Bioanalysis 4 (6), 633-642 (2012)
  • Author:
    Dziedzic J; Fox SJ; Fox T; Tautermann CS; Skylaris C-K
    Title:
    Large-scale DFT calculations in implicit solvent-A case study on the T4 lysozyme L99A/M102Q protein.
    Source:
    Int J Quantum Chem Article in Press (2012)
  • Author:
    Zhang L; Li Z; Wang X-J; Yee N; Senanayake C-H
    Title:
    Regioselective synthesis of polysubstituted N 2-alkylanyl-1,2,3-triazoles via 4-bromo-5-iodo-1,2,3-triazole.
    Source:
    Synlett 23 (7), 1052-1056 (2012)
  • Author:
    Feil SC; Hamilton S; Krippner GY; Lin B; Luttick A; McConnell DB; Nearn R; Parker MW; Ryan J; Stanislawski PC; Tucker SP; Watson KG; Morton CJ
    Title:
    An orally available 5-ethoxybenzisoxazole capsid binder with clinical activity against human rhinovirus.
    Source:
    ACS Med Chem Lett 3 (4), 303-307 (2012)
  • Author:
    Bantscheff M; Hobson S; Kuster B
    Title:
    Affinity purification of proteins binding to kinase inhibitors immobilized on self-assembling monolayers.
    Source:
    Methods Mol Biol 795, 149-160 (2012)
  • Author:
    Cozma A; Vlase L; Ignast A; Zaharia V; Gocan S; Grinberg N
    Title:
    Prediction of the lipophilicity of eight new p-toluenesulfonyl-hydrazinothiazole and hydrazine-bis-thiazole derivatives: A comparison between RP-HPTLC and RP-HPLC.
    Source:
    J Liq Chromatogr Relat Technol 35 (4), 590-601 (2012)
    Abstract:
    Using RP-HPTLC and RP-HPLC and a methanol-water mixture as the mobile phase, eight new p-toluenesulfonyl-hydrazinothiazole and hydrazine-bis-thiazole derivatives were studied. The linear correlation between R Mw, k W and methanol/water ratios showed high values, for the correlation coefficient R 2. The chromatographic hydrophobic index ? 0 was determined by using intercept and slope, the obtained values ranging between 60 and 98. A good linear correlation was obtained between R Mw, logk w, and slope. The log P values were calculated using database (Toronto, Canada). The matrices were formed with R Mw, logk w and logP and were subjected to principal component analysis (PCA). The best way to extract information from PCA was graphically, by plotting the obtained matrices. By analyzing the scores, the compounds can be grouped in two: the first group contains three compounds that have a phenyl moiety while the second group comprises other five compounds that contain: methyl, chlor-methyl, acetyl, and ethylic ester.
  • Author:
    Seeliger D; Soeroes S; Klingberg R; Schwarzer D; Grubmueller H; Fischle W
    Title:
    Quantitative assessment of protein interaction with methyl-lysine analogues by hybrid computational and experimental approaches.
    Source:
    ACS Chem Biol 7 (1), 150-154 (2012)
    Abstract:
    In cases where binding ligands of proteins are not easily available, structural analogues are often used. For example, in the analysis of proteins recognizing different methyl-lysine residues in histones, methyl-lysine analogues based on methyl-amino-alkylated cysteine residues have been introduced. Whether these are close enough to justify quantitative interpretation of binding experiments is however questionable. To systematically address this issue, we developed, applied, and assessed a hybrid computational/experimental approach that extracts the binding free energy difference between the native ligand (methyl-lysine) and the analogue (methyl-amino-alkylated cysteine) from a thermodynamic cycle. Our results indicate that measured and calculated binding differences are in very good agreement and therefore allow the correction of measured affinities of the analogues. We suggest that quantitative binding parameters for defined ligands in general can be derived by this method with remarkable accuracy.
  • Author:
    Reeves JT; Tan Z; Han ZS; Li G; Zhang Y; Xu Y; Reeves DC; Gonnella NC; Ma S; Lee H; Lu BZ; Senanayake C
    Title:
    Direct titanium-mediated conversion of ketones into enamides with ammonia and acetic anhydride.
    Source:
    Angew Chem Int Ed 51 (6), 1400-1404 (2012)
    Abstract:
    A one-step conversion of ketones into N-acetyl enamides was developed. The process employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates diverse functional groups. The addition of edte (N,N,N ,N -tetrakis(2-hydroxyethyl)ethylenediamine) prior to workup enables water solubilization of Ti alkoxides and allows a simple extractive workup.
  • Author:
    Groselj U; Kralj D; Wagger J; Dahmann G; Stanovnik B; Svete J
    Title:
    Synthesis of 3-(2-aminoethyl)-5-hydroxy-1H-pyrazole derivates.
    Source:
    Arkivoc 2012 (3), 49-65 (2012)
  • Author:
    Whelan G; Eichele G; Kreidl E; Wutz G; Peters J-M; Egner A
    Title:
    Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericenteric heterochromatin.
    Source:
    EMBO J 31 (1), 71-82 (2012)
  • Author:
    Vazari A; Ganim Z; Tokmakoff A
    Title:
    Vibrational excitons in ionophores: experimental probes for quantum coherence-assisted ion transport and selectivity in ion channels.
    Source:
    New J Phys 13 (2011)
  • Author:
    Zhang Y; Chitale S; Goyal N; Li G; Lu BZ; Han ZS; Shen S; Ma S; Grinberg N; Lee H; Senanayake CH
    Title:
    Asymmetric synthesis of sulfinamides using (-)-quinine as chiral auxiliary.
    Source:
    J Org Chem 77 (1), 690-695 (2012)
    Abstract:
    A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.
  • Author:
    Latli B; Byrne D; Nummy L; Krishnamurthy D; Senanayake CH
    Title:
    Synthesis of potent lymphocyte function-associated function-1 inhibitors labeled with carbon-14 and deuterium. Part 1.
    Source:
    J Label Compd Radiopharm 54 (12), 763-768 (2011)
  • Author:
    Klebe G; Koester H; Craan T; Brass S; Heine A; Herhaus Ch; Zentgraf M; Neumann L
    Title:
    A smal nonrule of 3 compatible fragment libarary provides high hit rate of endothiapepsin crystal structures with various fragment chemopypes.
    Source:
    J Med Chem 54 (22), 7784-7796 (2011)
  • Author:
    Latli B; Hrapchak M; Xu Y; Qiu F; Krishnamurthy D; Senanayake C-H
    Title:
    Synthesis of a highly potent leukocyte function associated antigen-1 antagonist and its metabolite labeled with stable isotopes and carbon-14, part 2.
    Source:
    J Label Compd Radiopharm 54 (13), 799-808 (2011)
    Abstract:
    (S)-2-[(R)-7-(3,5-Dichlorophenyl)-5-methyl-6-oxo-5-(4- trifluoromethoxybenzyl)-6,7-dihydro-5H-imidazo[1, 2-a]imidazole-3-sulfonylamino] -proprionamide (1), a potent lymphocyte function-associated antigen-1 antagonist and its sulfonamide metabolite (2) labeled with stable isotopes and carbon-14 were prepared for Drug Metabolism and PharmacoKinetics and other studies. A long linear route was used to prepare [ 13C 2, 2H 3]-(1) using [3,3,3- 2H]-D-alanine and [ 13C 2]-glycine in 15 steps and 2.5% overall yield. With the availability of [ 13C 6]-3,5-dichloroaniline, the sulfonamide [ 13C 6]-(2) was prepared in 12 steps and in 5.6% overall yield. For the carbon-14 synthesis, a six-step synthesis gave both compounds [ 14C]-(1) and [ 14C]-(2) from the common sulfonyl chloride intermediate [ 14C]-(15) in 18% and 4% radiochemical yields and specific activities of 44 and 40.5 mCi/mmol, respectively.
  • Author:
    Bantscheff M; Hobson S; Kuster B
    Title:
    Affinity purification of proteins binding to kinase inhibitors immobilized on self-assembling monolayers.
    Source:
    Methods Mol Biol 795, 149-160 (2012)
    Abstract:
    Kinase inhibitors represent a relatively new class of drugs that offer novel therapies targeting specific-malfunctioning kinase-mediated signaling pathways in oncology and potentially inflammation. As the ATP binding sites of the â^500 human kinases are structurally conserved and because most current drugs target the ATP binding site, there is a need to profile all the kinases that a drug may bind and/or inhibit. We have developed a chemical proteomics method that affinity purifies kinases from cell or tissue lysates using kinase inhibitors immobilized on self-assembling monolayers. The method can be applied to assess the selectivity of a given kinase inhibitor and thus to guide its preclinical or clinical development.
  • Author:
    Ma Sh; Shen Sh; Han Zh; Xu Y; Lee H; Krishnamurthy Dh; Senanayake Ch; Grinberg N
    Title:
    Determination of the absolute configuration of 3-amino-3-(tetrahydrofuran) carboxylic acid by vibrational circular dichroism and DFT calculation.
    Source:
    Stud Univ Babes-Bolyai Chem 56 (1), 221-228 (2011)
  • Author:
    Fandrick DR; Saha J; Fandrick KR; Sanyal S; Ogikubo J; Lee H; Roschangar F; Song JJ; Senanayake CH
    Title:
    Zinc-catalyzed allenylations of adehydes and ketones.
    Source:
    Org Lett 13 (20), 5616-5619 (2011)
  • Author:
    Lagace I; White PW; Bousquet C; Dansereau N; Doe F; Linas-Brunet M; Marquis M; Massariol M-J; Maurice R; Spickler C; Thibeault D; Triki I; Zhao S; Kukolj G
    Title:
    In vitro resistance profile of the hepatitis C virus NS3 protease inhibitor BI 201335.
    Source:
    Antimicrob Agents Chemother 56 (1), 569-572 (2012)
    Abstract:
    The in vitro resistance profile of BI 201335 was evaluated through selection and characterization of variants in genotype 1a (GT 1a) and genotype 1b (GT 1b) replicons. NS3 R155K and D168V were the most frequently observed resistant variants. Phenotypic characterization of the mutants revealed shifts in sensitivity specific to BI 201335 that did not alter susceptibility to alpha interferon. In contrast to macrocyclic and covalent protease inhibitors, changes at V36, T54, F43, and Q80 did not confer resistance to BI 201335.
  • Author:
    Yashio K; Katayama Y; Takashima T; Ishiguro N; Doi H; Suzuki M; Wada Y; Tamai I; Watanabe Y
    Title:
    Synthesis of [11C]uric acid, using [11C]phosgene, as a possible biomarker in PET imaging for diagnosis of gout.
    Source:
    Bioorg Med Chem Lett 22 (1), 11-119 (2012)
    Abstract:
    The synthesis and in vivo evaluation of 11C -labeled uric acid ([11C]1), a potential imaging agent for the diagnosis of urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [11C]1 was achieved by reacting 5,6-diaminouracil (2) with 11C-labeled phosgene ([11C]COCl2). The radiochemical yield of [11C]1 was 37 ± 7% (decay-corrected based on [11C]COCl2) with specific radioactivities of 96-152 GBq/?mol at the end of synthesis (n = 6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30 min with &gt;98% radiochemical purity. Second, the synthetic approach to [11C]1 was optimized using 5,6-diaminouracil sulfate (3) with [11C]COCl2 in the presence of 1,8-bis(dimethylamino)naphthalene. [11C]1 was synthesized in 36 ± 6% radiochemical yield, 89-142 GBq/?mol of specific radioactivities, and 98% radiochemical purity by this method (n = 5). This allowed the synthesis of [11C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [11C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [11C]1 has been developed, and preliminary PET evaluation of [11C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia.
  • Author:
    Ganim Z; Tokmakoff A; Vaziri A
    Title:
    Vibrational excitons in ionophores: Experimental probes for quantum coherence-assisted ion transport and selectivity in ion channels.
    Source:
    New J Phys 13 art.no. 113030 (2011)
    Abstract:
    Despite there being a large body of work, the exact molecular details underlying ion selectivity and transport in the potassium channel have not been fully uncovered. One major reason has been the lack of experimental methods that can probe these mechanisms dynamically on their biologically relevant timescales. Recently, it was suggested that quantum coherence and its interplay with thermal vibration might be involved in mediating ion selectivity and transport. In this paper, we present an experimental strategy for using time-resolved infrared spectroscopy to investigate these effects. We show the feasibility by demonstrating the infrared (IR) absorption and Raman spectroscopic signatures of the potassium-binding model molecules that mimic the transient interactions of potassium with binding sites of the selectivity filter during ion conduction. In addition to guiding our experiments on the real system, we have performed molecular dynamic-based simulations of the FTIR and two-dimensional IR (2DIR) spectra of the entire KcsA complex, which is the largest complex for which such modeling has been performed. We found that by combining isotope labeling with 2DIR spectroscopy, the signatures of potassium
  • Author:
    Demir-Kavuk O; Benzien J; Muegge I; Knapp EW
    Title:
    DemQSAR predicting human volume of distribution and clearance of drug.
    Source:
    J Comput Aided Mol Des 25 (12), 1121-1133 (2011)
    Abstract:
    In silico methods characterizing molecular compounds with respect to pharmacologically relevant properties can accelerate the identification of new drugs and reduce their development costs. Quantitative structure-activity/-property relationship (QSAR/QSPR) correlate structure and physico-chemical properties of molecular compounds with a specific functional activity/property under study. Typically a large number of molecular features are generated for the compounds. In many cases the number of generated features exceeds the number of molecular compounds with known property values that are available for learning. Machine learning methods tend to overfit the training data in such situations, i.e. the method adjusts to very specific features of the training data, which are not characteristic for the considered property. This problem can be alleviated by diminishing the influence of unimportant, redundant or even misleading features. A better strategy is to eliminate such features completely. Ideally, a molecular property can be described by a small number of features that are chemically interpretable. The purpose of the present contribution is to provide a predictive modeling approach, which combines feature generation, feature selection, model building and control of overtraining into a single application called DemQSAR. DemQSAR is used to predict human volume of distribution (VDss) and human clearance (CL). To control overtraining, quadratic and linear regularization terms were employed. A recursive feature selection approach is used to reduce the number of descriptors. The prediction performance is as good as the best predictions reported in the recent literature. The example presented here demonstrates that DemQSAR can generate a model that uses very few features while maintaining high predictive power. A standalone DemQSAR Java application for model building of any user defined property as well as a web interface for the prediction of human VDss and CL is available on the webpage of DemPRED: http://agknapp.chemie.fu-berlin.de/dempred/.
  • Author:
    Riniker S; Christ CD; Hansen HS; Huenenberger PH; Oostenbrink C; Steiner D; van Gunsteren WF
    Title:
    Calculation of relative free energies for ligand-protein binding, solvation and conformational transitions using the GROMOS software.
    Source:
    J Phys Chem B 115 (46), 13570-13577 (2011)
    Abstract:
    The calculation of the relative free energies of ligand-protein binding, of solvation for different compounds, and of different conformational states of a polypeptide is of considerable interest in the design or selection of potential enzyme inhibitors. Since such processes in aqueous solution generally comprise energetic and entropic contributions from many molecular configurations, adequate sampling of the relevant parts of configurational space is required and can be achieved through molecular dynamics simulations. Various techniques to obtain converged ensemble averages and their implementation in the GROMOS software for biomolecular simulation are discussed, and examples of their application to biomolecules in aqueous solution are given.
  • Author:
    Wallnoefer HG; Liedl KR; Fox T
    Title:
    A GRID-derived water network stabilizes molecular dynamics computer simulations of a protease.
    Source:
    J Chem Inform Modeling 51 (11), 2860-2867 (2011)
    Abstract:
    Structural water molecules are crucial for the stability and function of proteins. Recently, we presented a molecular dynamics (MD) study on blood coagulation factor Xa (fXa) to investigate the effect of water molecules on the flexibility of the protein structure. We showed that neglecting important water positions at the outset of the simulation leads to severe structural distortions during the MD simulations: A stable trajectory was obtained with a water set that was derived from all 73 X-ray structures of the protein. However, for many proteins of interest, only limited structural data is available, which precludes the merging of information from many X-ray structures. Here, we show that an in silico assembled water network, derived from molecular interaction fields generated with the GRID program, is a viable alternative to X-ray data. MD simulations with the GRID water set show a significantly improved stability over alternative setups without water or the X-ray resolved water molecules in the starting structure. The performance is comparable to a water setup derived from a recently presented clustering approach.
  • Author:
    Kneissl B; Mueller SC; Tautermann CS; Hildebrandt A
    Title:
    String kernels and high-quality data set for improved prediction of kinked helices in alpha-helical memnbrane proteins.
    Source:
    J Chem Inform Modeling 51 (11), 3017-3025 (2011)
    Abstract:
    The reasons for distortions from optimal ?-helical geometry are widely unknown, but their influences on structural changes of proteins are significant. Hence, their prediction is a crucial problem in structural bioinformatics. For the particular case of kink prediction, we generated a data set of 132 membrane proteins containing 1014 manually labeled helices and examined the environment of kinks. Our sequence analysis confirms the great relevance of proline and reveals disproportionately high occurrences of glycine and serine at kink positions. The structural analysis shows significantly different solvent accessible surface area mean values for kinked and nonkinked helices. More important, we used this data set to validate string kernels for support vector machines as a new kink prediction method. Applying the new predictor, about 80% of all helices could be correctly predicted as kinked or nonkinked even when focusing on small helical fragments. The results exceed recently reported accuracies of alternative approaches and are a consequence of both the method and the data set.
  • Author:
    Fox SJ; Pittock C; Fox T; Tautermann CS; Malcolm N; Skylaris C-K
    Title:
    Electrostatic embedding in large-scale first principles quantum mechanical calculations on biomolecules.
    Source:
    J Chem Phys 135 (22), 24107 art.no.224107 (2011)
    Abstract:
    Biomolecular simulations with atomistic detail are often required to describe interactions with chemical accuracy for applications such as the calculation of free energies of binding or chemical reactions in enzymes. Force fields are typically used for this task but these rely on extensive parameterisation which in cases can lead to limited accuracy and transferability, for example for ligands with unusual functional groups. These limitations can be overcome with first principles calculations with methods such as density functional theory (DFT) but at a much higher computational cost. The use of electrostatic embedding can significantly reduce this cost by representing a portion of the simulated system in terms of highly localised charge distributions. These classical charge distributions are electrostatically coupled with the quantum system and represent the effect of the environment in which the quantum system is embedded. In this paper we describe and evaluate such an embedding scheme in which the polarisation of the electronic density by the embedding charges occurs self-consistently during the calculation of the density. We have implemented this scheme in a linear-scaling DFT program as our aim is to treat with DFT entire biomolecules (such as proteins) and large portions of the solvent. We test this approach in the calculation of interaction energies of ligands with biomolecules and solvent and investigate under what conditions these can be obtained with the same level of accuracy as when the entire system is described by DFT, for a variety of neutral and charged species.
  • Author:
    Vlad C; Lindner K; Karreman C; Schicknecht S; Leist M; Tomczyk N; Rontree J; Langridge J; Danzer K; Ciossek T; Petre A; Gross ML; Hengerer B; Przybylski M
    Title:
    Autoproteolytic fragments are intermediates in the oligomerization/aggregation of the Parkinson's disease protein alpha-synuclein as revealed by ion mobility mass spectrometry.
    Source:
    ChemBioChem 12 (18), 2740-2744 (2011)
  • Author:
    Taus Th; Koecher Th; Pichler P; Paschke C; Schmidt A; Henrich Ch; Mechtler K
    Title:
    Universal and confident phosphorylation site localization using phosphoRS.
    Source:
    J Proteome Res 10 (12), 5354-5362 (2011)
    Abstract:
    An algorithm for the assignment of phosphorylation sites in peptides is described. The program uses tandem mass spectrometry data in conjunction with the respective peptide sequences to calculate site probabilities for all potential phosphorylation sites. Tandem mass spectra from synthetic phosphopeptides were used for optimization of the scoring parameters employing all commonly used fragmentation techniques. Calculation of probabilities was adapted to the different fragmentation methods and to the maximum mass deviation of the analysis. The software includes a novel approach to peak extraction, required for matching experimental data to the theoretical values of all isoforms, by defining individual peak depths for the different regions of the tandem mass spectrum. Mixtures of synthetic phosphopeptides were used to validate the program by calculation of its false localization rate versus site probability cutoff characteristic. Notably, the empirical obtained precision was higher than indicated by the applied probability cutoff. In addition, the performance of the algorithm was compared to existing approaches to site localization such as Ascore. In order to assess the practical applicability of the algorithm to large data sets, phosphopeptides from a biological sample were analyzed, localizing more than 3000 nonredundant phosphorylation sites. Finally, the results obtained for the different fragmentation methods and localization tools were compared and discussed.
  • Author:
    Taylor StJ; Abeywardane A; Liang Sh; Muegge I; Padyana AK; Xiong Zh; Hill-Drzewi M; Farmer B; Li X; Collins B; Li JX; Heim-Riether A; Proudfoot J; Zhang Q; Goldberg D; Zuvela-Jelaska L; Zaher H; Li J; Farrow NA
    Title:
    Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13.
    Source:
    J Med Chem 54 (23), 8174-8187 (2011)
    Abstract:
    Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.
  • Author:
    Buchheit D; Schmitt EI; Bischoff D; Ebner T; Bureik M
    Title:
    S-glucuronidation of 7-mercapto-4-methylcoumarin by human UDP glycosyltransferases in genetically engineered fission yeast cells
    Source:
    Biol Chem 392 (12), 1089-1095 (2011)
    Abstract:
    Human UDP glycosyltransferases (UGTs) play an important role in xenobiotic detoxification. They increase the solubility of their substrates by adding a sugar moiety (such as glucuronic acid) to different functional entities (such as hydroxyl groups). The aim of this study was to investigate how glucuronidation of a standard substrate is affected by a change of the hetero-atom at the conjugation site. For this purpose, we compared the in vitro glucuronidation rates of 4-methylumbelliferone and 7-mercapto-4-methylcoumarin, respectively. Human liver microsomes catalyzed the S-glucuronidation of 7-mercapto-4- methylcoumarin almost as efficient as the O-glucuronidation of 4-methylumbelliferone. When testing isoenzyme specificity by whole cell biotransformation with fission yeast strains that recombinantly express all 19 human members of the UGT1 and UGT2 families, it was found that 13 isoenzymes were able to glucuronidate 7-mercapto-4-methylcoumarin, with five of them being specific for this substrate and the other eight also converting 4-methylumbelliferone under these conditions. The remaining six UGTs did not accept either substrate. Out of the eight isoenzymes that glucuronidated both substrates, four catalyzed both reactions approximately to the same extent, while three displayed higher conversion rates towards 4-methylumbelliferone and one preferred 7-mercapto-4-methylcoumarin. These data suggest that 7-mercapto-4-methylcoumarin is a convenient new standard substrate for monitoring S-glucuronidation.
  • Author:
    Fuchs JE; Spitzer GM; Javed A; Biela A; Kreutz C; Wellenzohn B; Liedl KR
    Title:
    Minor groove binders and drugs targeting proteins cover complementary regions in chemical shape space.
    Source:
    J Chem Inform Modeling 51 (9), 2223-2232 (2011)
    Abstract:
    DNA minor groove binders (MGBs) are known to influence gene expression and are therefore widely studied to explore their therapeutic potential. We identified shape-based virtual screening with ROCS as a highly effective computational approach to enrich known MGBs in top-ranked molecules. Discovery of ten previously unknown MGBs by shape-based screening further confirmed the relevance of ligand shape for minor groove affinity. Based on experimental testing we propose three simple rules (at least two positive charges, four nitrogen atoms, and one aromatic ring) as filters to reach even better enrichment of true positives in ROCS hit lists. Interestingly, shape-based ranking of MGBs versus FDA-approved drugs again leads to high enrichment rates, indicating complementary coverage of chemical shape space and indicating minor groove affinity to be unfavorable for approval of drugs targeting proteins.
  • Author:
    Fischer JR; Lessel U; Rarey M
    Title:
    Improving similarity-driven library design: Customized matching and regioselective feature trees.
    Source:
    J Chem Inform Modeling 51 (9), 2156-2163 (2011)
    Abstract:
    Reduced graph descriptors, like feature trees, are frequently applied in cases where the relative arrangement of functional groups is more important than exact substructure matches. Due to their ability to deal with fragmented molecules, they are well-suited for fragment space search and library design. We recently presented LoFT, a novel focused library design approach based on feature trees. During evaluation two drawbacks of the reduced graph descriptor were discovered: First, regioisomeric substructures cannot be distinguished in feature tree mappings which results in a large information loss especially when connecting R-groups to cores. Second, the automatic matching procedure might result in undesired alignments, since the knowledge on what is considered as core by the user is not taken into account. In the following, we will present two approaches to overcome those drawbacks. The generation of the feature trees is modified, so that different arene substitution patterns can be recognized and a customized matching is introduced, allowing the user to determine the parts of the query, where the reagents are allowed to match. Subsequently we investigate the improvements on library design by reviewing the design scenarios which were already used for the evaluation of LoFT.
  • Author:
    Betageri R; Gilmore T; Kuzmich D; Kirrane TM; Bentzien J; Wiedenmayer D; Bekkali Y; Regan J; Berry A; Latli B; Kukulka AJ; Fadra TN; Nelson RM; Goldrick S; Zuvela-Jelaska L; Souza D; Pelletier J; Dinallo R; Panzenbeck M; Torcellini C; Lee H; Pack E; Harcken C; Nabozny G; Thomson DS
    Title:
    Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.
    Source:
    Bioorg Med Chem Lett 21 (22), 6842-6851 (2011)
    Abstract:
    We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
  • Author:
    Janjic M; Prebil R; Groselj U; Kralj D; Malavsic C; Golobic A; Stare K; Stanovnik B; Svete J; Dahmann G
    Title:
    A simple synthesis of 5-(2-aminophenyl)-1H-pyrazoles.
    Source:
    Helv Chim Acta 94 (9), 1703-1717 (2011)
    Abstract:
    A four-step synthesis of 1-substituted 5-(2-aminophenyl)-1H-pyrazoles 5 as a novel type of histamine analogs and versatile building blocks for further transformations was developed. The synthesis starts from commercially available 2-nitroacetophenone (12), which is converted into the enamino ketone 13 as the key intermediate. Cyclization of the key intermediate 13 with monosubstituted hydrazines 14a-14l afforded the 5-(2-nitrophenyl)-1H-pyrazoles 17a-17l. Finally, catalytic hydrogenation of the nitro compounds 17a, 17c-17e, and 17g-17j furnished the title compounds 5a, 5c-5e, and 5g-5j, respectively, in good yields. As demonstrated by some further transformations, additional functionalization of compounds 17 and 5 is feasible, either by electrophilic substitution at C(4) of the pyrazole ring, or at the NH2 group.
  • Author:
    Wang X-J; Frutos RP; Zhang L; Sun X; Xu Y; Wirth T; Nicola T; Nummy LJ; Krishnamurthy D; Bussaca CA; Yee N; Senanayake CH
    Title:
    Asymmetric synthesis of LFA-1 inhibitor BIRT2584 on metric ton scale.
    Source:
    Org Process Res Dev 15 (5), 1185-1191 (2011)
    Abstract:
    The synthesis of LFA-1 inhibitor BIRT2584 on metric-ton scale was accomplished by means of a safe and robust process. Highlights of the process include the asymmetric synthesis of the key advanced intermediate by implementation of Seebach's self-regeneration of stereocenters principle, and a Ph3PCl2-induced dehydration of a critical urea followed by a regioselective bromination to give the elaborated 1H-imidazo[1,2-aimidazol-2- one. A sulfonyl chloride intermediate was produced through Br/Mg exchange of iodoimidazole followed by addition to SO2 in THF and subsequent oxidation. In a one-pot operation, the sulfonyl chloride was directly reacted with l-alaninamide using NaOH as base in aqueous DMF/THF to give BIRT2584.
  • Author:
    Tang W; Wei X; Yee NK; Patel N; Lee H; Savoie J; Senanayake CH
    Title:
    A practical asymmetric synthesis of isopropyl (1R,2S)-dehydrocoronamate.
    Source:
    Org Process Res Dev 15 (5), 1207-1211 (2011)
    Abstract:
    A novel asymmetric synthesis of isopropyl (1R,2S)-dehydrocoronamate is described from (S)-1,2,4-butanetriol as the starting material in 28% overall yield. Highlights of this synthetic route include selective cyclopropanation between chiral cyclic sulfate 5 and diisopropyl malonate (8c), formation of vinylcyclopropane 3c via elimination of halide 4c, selective monohydrolysis of diisopropyl ester 3c, and Curtius rearrangement of acid 10 to form isopropyl (1R,2S)-dehydrocoronamate TsOH salt 13 in >99% ee. With the involvement of only three isolations, this chromatography-free process provides a rapid and practical access to (1R,2S)-1-amino-2-vinylcyclopropane-1-carboxylic acid derivatives.
  • Author:
    Zang Y; Kammerer B; Eisenkolb M; Lohr K; Kiefer H
    Title:
    Towards protein crystallization as a process step in downstream processing of therapeutic antibodies: Screening and optimization at microbatch scale.
    Source:
    PLoS ONE 6 (9) art.no. 25282 (2011)
    Abstract:
    Crystallization conditions of an intact monoclonal IgG4 (immunoglobulin G, subclass 4) antibody were established in vapor diffusion mode by sparse matrix screening and subsequent optimization. The procedure was transferred to microbatch conditions and a phase diagram was built showing surprisingly low solubility of the antibody at equilibrium. With up-scaling to process scale in mind, purification efficiency of the crystallization step was investigated. Added model protein contaminants were excluded from the crystals to more than 95%. No measurable loss of Fc-binding activity was observed in the crystallized and redissolved antibody. Conditions could be adapted to crystallize the antibody directly from concentrated and diafiltrated cell culture supernatant, showing purification efficiency similar to that of Protein A chromatography. We conclude that crystallization has the potential to be included in downstream processing as a low-cost purification or formulation step.
  • Author:
    Gravel M; Sanchez-Larios E; Thai K; Bilodeau F
    Title:
    Highly enantioselective intermolecular stetter reactions of beta-aryl acceptors: alpha-ketoester moiety as handle for activation and synthetic manipulations.
    Source:
    Org Lett 13 (18), 4942-4945 (2011)
    Abstract:
    The use of beta,gamma-unsaturated-alpha-ketoesters in the intermolecular Stetter reaction furnishes 1,2,5-tricarbonyl compounds in high yield and excellent enantioselectivity. The alpha,delta-diketoesters generated using this methodology serve as useful synthetic building blocks via chemo- and diastereoselective transformations.
  • Author:
    Jiang X; Gold D; Kolaczyk ED
    Title:
    Network-based auto-probit modeling for protein function prediction.
    Source:
    Biometrics 67 (3), 958-966 (2011)
    Abstract:
    Summary Predicting the functional roles of proteins based on various genome-wide data, such as protein-protein association networks, has become a canonical problem in computational biology. Approaching this task as a binary classification problem, we develop a network-based extension of the spatial auto-probit model. In particular, we develop a hierarchical Bayesian probit-based framework for modeling binary network-indexed processes, with a latent multivariate conditional autoregressive Gaussian process. The latter allows for the easy incorporation of protein-protein association network topologies-either binary or weighted-in modeling protein functional similarity. We use this framework to predict protein functions, for functions defined as terms in the Gene Ontology (GO) database, a popular rigorous vocabulary for biological functionality. Furthermore, we show how a natural extension of this framework can be used to model and correct for the high percentage of false negative labels in training data derived from GO, a serious shortcoming endemic to biological databases of this type. Our method performance is evaluated and compared with standard algorithms on weighted yeast protein-protein association networks, extracted from a recently developed integrative database called Search Tool for the Retrieval of INteracting Genes/proteins (STRING). Results show that our basic method is competitive with these other methods, and that the extended method-incorporating the uncertainty in negative labels among the training data-can yield nontrivial improvements in predictive accuracy.
  • Author:
    Kley JT; Mack J; Hamilton B; Scheuerer St; Redemann N
    Title:
    Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure.
    Source:
    Bioorg Med Chem Lett 21 (19), 5924-5927 (2011)
    Abstract:
    Based on a high-throughput screen, cyclopentanecarboxanilides were identified as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). Starting from initial hits we aimed at generating a tool compound suitable for the in vivo validation of FAS as a therapeutic target. Optimisation yielded BI 99179 which is characterised by high potency, remarkably high selectivity and significant exposure (both peripheral and central) upon oral administration in rats. - DERWENT Abstract - In this study, cyclopentanecarboxanilides (5-28) were identified based on a high-throughput screen and evaluated as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). The (1R,3S) N-[4-(1,3-benzoxazol 2-yl)phenyl]-N-methyl 3-propanamidocyclopentane 1-carboxamide (13) which proved to be the most potent compound has a significantly lower c log P value as compared to (1R,3S)-3-acetamido N-methyl N-(4-phenylphenyl) cyclopentane 1-carboxamide (5). Compound (13) also proved to be the most potent derivative in the mouse N-42 cellular assay. Compound (13) showed no significant LDH release in the cytotoxicity assay up to 30 uM compound concentrations. Favorable in-vitro pharmacokinetic parameters of (13) appeared to translate into a low clearance and a moderate Vd following i.v. administration to rats. Systematic modifications of all other parts of the molecule revealed generally steep SAR except for R1 and R2. Gratifyingly, the (1R,3S) N-[4-(1,3-benzoxazol 2-yl)phenyl]-N-methyl 3-propanamidocyclopentane 1-carboxamide (13) which proved to be the most potent compound has a significantly lower c log P value as compared to (1R,3S)-3-acetamido N-methyl N-(4-phenylphenyl) cyclopentane 1-carboxamide (5) (c log P=3.1 vs. 3.6, respectively). Compound (13) also proved to be the most potent derivative with an IC50 of 0.6 uM in the mouse N-42 cellular assay. Compound (13) showed no significant LDH release in the cytotoxicity assay up to 30 uM compound concentrations. Favorable in-vitro pharmacokinetic parameters of (13) (CaCo-2 permeability: 94 x 10 power -6 cm/sec with no indication for the involvement of efflux transporters; high metabolic stability in rat and human mirosomes: less than 27% and less than 26% of the respective liver-blood-flow QH: rat plasma protein binding: 97.6%) appeared to translate into a low clearance (CL=8.2 ml/min/kg) and a moderate Vd (Vss=1.6 l/kg) following i.v. administration to male Han/Wistar rats. Notably similarly high compound levels in plasma and brain were seen upon p.o. administration (the ratio CCSF: Cbrain of approximately 4% can be rationalized by protein binding which was determined to be 97.6% with rat plasma). The relatively low aqueous solubility of (13) (5 ug/ml at pH 7.4) did not compromise the compound's good pharmacokinetic properties.
  • Author:
    Busacca CA; Fandrick DR; Song JJ; Senanayake CH
    Title:
    The growing impact of catalysis in the pharmaceutical industry.
    Source:
    Adv Synth Catal 353 (11-12), 1825-1864 (2011)
    Abstract:
    Catalysis has become increasingly important for the pharmaceutical industry. Catalysis is a critical technology that enables economical and environmentally-sound manufacturing processes. The development of a viable catalytic process for industrial scales is a complex task that requires the collaboration of multiple disciplines. In this article, a number of selected, noteworthy industrial examples are discussed to showcase the catalytic technologies that have been successfully practiced on large scales for active pharmaceutical ingredient (API) synthesis, involving transition metal catalysis, biocatalysis and organocatalysis. In addition, several examples of potential and future catalytic transformations are included which can be utilized in pharmaceutical industry in large-scale operational settings.
  • Author:
    Bieler M; Heilker R; Koppen H; Schneider G
    Title:
    Assay related target similarity (ARTS) - Chemogenomics approach for quantitative comparison of biological targets.
    Source:
    J Chem Inform Modeling 51 (8), 1897-1905 (2011)
    Abstract:
    Computer-based chemogenomics approaches compare macromolecular drug targets based on their amino acid sequences or derived properties, by similarity of their ligands, or according to ligand-target interaction models. Here we present ARTS (Assay Related Target Similarity) as a quantitative index that estimates target similarity directly from measured affinities of a set of probe compounds. This approach reduces the risk of deducing artificial target relationships from mutually inactive compounds. ARTS implements a scoring scheme that matches intertarget similarity based on dose-response measurements. While all experimentally derived target similarities have a tendency to be data set-dependent, we demonstrate that ARTS depends less on the used data set than the commonly used Pearson correlation or Tanimoto index.
  • Author:
    Welander H; Bontha SV; Karlsson M; Naesstroem T; Nikolajeff F; Danzer K; Kostka M; Kalimo H; Lannfelt N; Ingelsson M; Bergstroem J
    Title:
    Gelsolin co-occurs with Lewy bodies in vivo and accelerates alpha-synuclein aggregation in vitro.
    Source:
    Biochem Biophys Res Commun 412 (1), 32-38 (2011)
    Abstract:
    Deposition of fibrillar ?-synuclein as Lewy bodies is the neuropathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Apart from ?-synuclein, these intraneuronal inclusions contain over 250 different proteins. The actin binding protein gelsolin, has previously been suggested to be part of the Lewy body, but its potential role in ?-synuclein aggregation remains unknown. Here, we studied the association between gelsolin and ?-synuclein in brain tissue from PD and DLB patients as well as in a cell model for ?-synuclein aggregation. Moreover, the potential effect of gelsolin on ?-synuclein fibrillization was also investigated. Our data demonstrate that gelsolin co-occured with ?-synuclein in Lewy bodies from affected human brain as well as with Lewy body-like inclusions in ?-synuclein over expressing cells. Furthermore, in the presence of calcium chloride, gelsolin was found to enhance the aggregation rate of ?-synuclein in vitro. Moreover, no apparent structural differences could be observed between fibrils formed in the presence or absence of gelsolin. Further studies on gelsolin and other Lewy body associated proteins are warranted to learn more about their potential role in the ?-synuclein aggregation process.
  • Author:
    Perdih P; Baskovc J; Dahmann G; Groselj U; Kocar D; Novak A; Stanovnik B; Svete J
    Title:
    Parallel synthesis of 1-substituted 5-(5-Oxopyrrolidin-3-yl)- 1H-pyrazole-4-carboxamides.
    Source:
    Synthesis (17), 2822-2832 (2011)
    Abstract:
    A parallel solution-phase synthesis of 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-carboxamide derivatives as conformationally constrained pyrazole analogues of histamine starting from itaconic acid was developed. The synthetic method comprises a five-step preparation of 1-substituted 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-carboxylic acids followed by parallel amidation with various primary and secondary amines to give a library of 24 histamine analogues in good overall yields and in very high purities. The method is general and substrate-independent. All the amidations proceed smoothly and no major difference in reactivity is observed with respect to the structures of the reactants.
  • Author:
    Han Zh; Busch R; Fandrick KR; Meyer A; Xu Y; Krishnamurthy DhK; Senanayake ChH
    Title:
    Asymmetric synthesis of diverse .alpha.,.alpha.-diarylmethylamines via aryl Grignard additions to chiral N-2,4,6-triisopropylbenzenesulfinylimines.
    Source:
    Tetrahedron 67 (37), 7035-7041 (2011)
    Abstract:
    A mild method has been developed for the asymmetric synthesis of a variety of chiral diarylmethylamines via the addition of aryl Grignard reagents to chiral N-2,4,6-triisopropylbenzenesulfinylimines in high yields and high diastereoselectivities. Higher stereoselectivity was obtained for most of the examples studied when the reactions are performed at ambient temperature as compared to cryogenic conditions. N-2,4,6-Triisopropylbenzenesulfinamide was shown to be the optimal chiral auxiliary as it provided higher diastereoselectivities when compared to the more commonly employed tert-butanesulfinamide or p-toluenesulfinamide in the synthesis of diarylmethylamine synthons. A rationale for the improved selectivity derived from the triisopropylbenzyl auxiliary is presented.
  • Author:
    Kredel S; Wolff M; Hobbie S; Bieler M; Gierschik P; Heilker R
    Title:
    High-content analysis of CCR2 antagonists on human primary monocytes.
    Source:
    J Biomol Screen 16 (7), 683-693 (2011)
    Abstract:
    The monocyte chemoattractant protein 1 (MCP-1)-driven activation of CC-type chemokine receptor 2 (CCR2) is one of the early key events to induce monocyte migration toward centers of inflammation. In this work, the authors analyzed MCP-1 internalization into primary human monocytes using partially automated liquid handling, automated fluorescence microscopic imaging, and a specific image analysis algorithm. A fluorophore-conjugated form of MCP-1 was rapidly endocytosed and retained by the monocytes. The CCR2 dependency of the MCP-1 internalization was demonstrated by the use of BMS CCR2 22, a CCR2-specific antagonist. The apparent inhibitory potencies of a series of small-molecule CCR2 antagonists were determined and compared in five assay formats, including the high-content analysis assay described in this work. Interestingly, some but not all antagonists showed markedly different inhibitory behaviors in the five readout systems, with an up to more than 100-fold difference between the highest and the lowest apparent inhibitory potencies. These findings raise the distinct possibility that some CCR2 antagonists are capable of discriminating between different functional states of the CCR2 receptor(s) and suggest strategies for the identification of functionally selective CCR2 antagonists with increased therapeutic advantage over nonselective antagonists.
  • Author:
    Boecker A; Bonneau PR; Edwards PJ
    Title:
    HTS promiscuity analyses for accelerating decision making.
    Source:
    J Biomol Screen 16 (7), 765-774 (2011)
    Abstract:
    Frequent hitters are compounds that are detected as a "hit" in multiple high-throughput screening (HTS) assays. Such behavior is specific (e. g., target family related) or unspecific (e. g., reactive compounds) or can result from a combination of such behaviors. Detecting such hits while predicting the underlying reason behind their promiscuous behavior is desirable because it provides valuable information not only about the compounds themselves but also about the assay methodology and target classes at hand. This information can also greatly reduce cost and time during HTS hit profiling. The present study exemplifies how to mine large HTS data repositories, such as the one at Boehringer Ingelheim, to identify frequent hitters, gain further insights into the causes of promiscuous behavior, and generate models for predicting promiscuous compounds. Applications of this approach are demonstrated using two recent large-scale HTS assays. The authors believe this analysis and its concrete applications are valuable tools for streamlining and accelerating decision-making processes during the course of hit discovery.
  • Author:
    Schultes S; de Graaf Ch; Berger H; Mayer M; Steffen A; Haaksma EEJ; de Esch IJP; Leurs R; Kraemer O
    Title:
    A medicinal chemistry perspective on melting point: Matched molecular pair analysis of the effects of simple descriptors on the melting points of drug like compounds.
    Source:
    13th Figon Dutch Medicine Days, Breukelen (Netherlands), Oct 3-5, 2011.MedChemComm 3 (5), 584-591 (2012)
    Abstract:
    The influence of simple molecular descriptors on the melting point temperature (T m) has been investigated using a matched molecular pair (MMP) analysis. This method has been used to identify small structural differences between pairs of molecules which are related to changes in T m. Our analysis shows that the number of hydrogen bond donors, hydrogen bond acceptors and rotatable bonds has a significant effect on the T m of a molecule. Hydrogen bond donors have the most pronounced effect. Furthermore, the studies reveal that not ClogP but rather the number of bromine and iodine atoms has a marked effect on the T m. The results of our MMP analysis are discussed within the context of drug solubility optimization.
  • Author:
    Kim S-H; de Mas N; Parlanti L; Lyngberg OK; Stroehlein G; Guo Z; Dambalas K; Rosso VW; Yang B-S; Girard KP; Manaloto ZA; D'Arasmo G; Frigerio FE; Wang W; Lu X; Bolgar MS; Gokhale M; Thakur AB
    Title:
    Synthesis, chromatographic purification and isolation of epothilone-folic acid conjagate BMS-753493.
    Source:
    Org Process Res Dev 15 (4), 797-809 (2011)
    Abstract:
    We describe the synthesis, chromatographic purification, and isolation of the epothilone-folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10-30 g) of cGMP quality BMS-753493.
  • Author:
    Zhang Y; Gao J; Li W; Lee H; Lu BZ; Senanayake CH
    Title:
    Synthesis of 8-arylquinolines via one-pot Pd-catalyzed borylation of quinoline-8-yl halides and subsequent suzukui miyaura coupling.
    Source:
    J Org Chem 76 (15), 6394-6400 (2011)
    Abstract:
    A one-pot process has been developed for the synthesis of 8-arylquinolines via Pd-catalyzed borylation of quinoline-8-yl halides and subsequent Suzuki-Miyaura coupling with aryl halides using n-BuPAd(2) as ligand. Yields of up to 98% were obtained.
  • Author:
    Li W; Gao JJ; Zhang YD; Tang WJ; Lee H; Fandrick KR; Lu B; Senanayake CH
    Title:
    A mild palladium-catalyzed suzuki coupling reaction of quinoline carboxylates with boronic acids.
    Source:
    Adv Synth Catal 353 (10), 1671-1675 (2011)
    Abstract:
    A palladium-catalyzed cross-coupling between aryl carboxylates and boronic acids has been achieved for the first time by taking advantage of the enhanced reactivity of quinoline 4-carboxylates. Also for the first time a Suzuki coupling reaction via a self-activation of boronic acids without addition of base is described. The reactions proceed under mild conditions (25-65 degrees C) to give excellent yields, and a wide range of functionalities is tolerated.
  • Author:
    Patel ND; Tang W; Sarvestani M; Wei X; Yee NK; Senanayake ChH
    Title:
    Facile and practical synthesis of N-acetyl enamides.
    Source:
    Abstr Pap Am Chem Soc 241 320-ORGN (2011)
  • Author:
    Huber JD; Guo X; Soleymanzadeh F; Swinamer A; Kennedy Ch; Kaplita P; Nagaraja N; Eikmeier Ch; Madwed JB; deLombaert St; Eldrup AB
    Title:
    Identification of a potent NHE1 inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat.
    Source:
    241st National Meeting and Exposition of the American Chemical Society (ACS), Anaheim (United States), Mar 27-31, 2011.Abstr Pap Am Chem Soc 241, 23-MEDI (2011)
  • Author:
    Riniker S; Christ CD; Hansen N; Mark AE; Nair PC; van Gunsteren WF
    Title:
    Comparison of enveloping distribution sampling and thermodynamic integration to calculate binding free energies of phenylethanolamine N-methyltransferase inhibitors.
    Source:
    J Chem Phys 135 (2), 024105 (2011)
    Abstract:
    The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. The more accurate and also computationally more demanding techniques are the so-called free energy methods which use conformational sampling from molecular dynamics or Monte Carlo simulations to generate thermodynamic averages. Two such widely applied methods are the thermodynamic integration (TI) and the recently introduced enveloping distribution sampling (EDS) methods. In both cases relative binding free energies are obtained through the alchemical perturbations of one ligand into another in water and inside the binding pocket of the protein. TI requires many separate simulations and the specification of a pathway along which the system is perturbed from one ligand to another. Using the EDS approach, only a single automatically derived reference state enveloping both end states needs to be sampled. In addition, the choice of an optimal pathway in TI calculations is not trivial and a poor choice may lead to poor convergence along the pathway. Given this, EDS is expected to be a valuable and computationally efficient alternative to TI. In this study, the performances of these two methods are compared using the binding of ten tetrahydroisoquinoline derivatives to phenylethanolamine N-transferase as an example. The ligands involve a diverse set of functional groups leading to a wide range of free energy differences. In addition, two different schemes to determine automatically the EDS reference state parameters and two different topology approaches are compared.
  • Author:
    Edwards PJ; Sturino C
    Title:
    Managing the liabilities arising from structural alerts: a safe philosophy for medicinal chemists.
    Source:
    Curr Med Chem 18 (20), 3116-3135 (2011)
    Abstract:
    Bioactivation of xenobiotics can, in certain circumstances, result in the formation of reactive electrophilic species. These reactive metabolites may covalently modify proteins and macromolecules and it has been suggested that protein modification is a key initial step in provoking idiosyncratic adverse drug reactions. Understanding these bioactivation pathways is critical in order to rationally design drug candidates with a lower propensity to form reactive intermediates. Herein, we provide an overview of the importance of Structural Alerts and bioactivation pathways and describe the creation of an in-house database as a tool aimed at informing medicinal chemists about these potential liabilities.
  • Author:
    Fandrick KR; Fandrick DR; Reeves JT; Gao J; Ma S; Li W; Lee H; Grinberg N; Lu B; Senanayake ChH
    Title:
    A general cooper-BINAP-catalyzed asymmetric propargylation of ketones with propargyl boronates.
    Source:
    J Am Chem Soc 133 (27), 10332-10335 (2011)
    Abstract:
    An operationally simple copper-BINAP-catalyzed, highly enantioselective propargylation of ketones is presented. The methodology was developed as an enantioselective process for methyl ethyl ketone and shown to be applicable to a wide variety of prochiral ketones. The resulting homopropargyl adducts are versatile latent carbonyls from which .gamma.-butyrolactones, .beta.-hydroxy methyl ketones, and .beta.-hydroxycarboxylates are readily obtained.
  • Author:
    Lo HY; Nemoto PA; Kim JM; Hao M-H; Qian KC; Farrow NA; Albaugh DR; Fowler DM; Schneiderman RD; Michael August E; Martin L; Hill-Drzewi M; Pullen SS; Takahashi H; de Lombaert S
    Title:
    Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P1) regioin.
    Source:
    Bioorg Med Chem Lett 21 (15), 4533-4539 (2011)
    Abstract:
    A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P1 hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P1 moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P1 replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
  • Author:
    Latli B; Hrapchak M; Seetharma R; Krishnamurthy Dh; Senanayake ChH
    Title:
    Chemical synthesis of allyl-[c-13(6)]-glucuronate
    Source:
    J Label Compd Radiopharm 54 (6), 337-339 (2011)
    Abstract:
    The synthesis of allyl-[c-13(6)]-glucuronate from .alpha.-D-[13C6]-glucose in five steps is described. Selective protection of the primary alcohol in the glucose with the bulky trityl group followed by acetylation in the same pot gave the fully protected sugar. Removal of the trityl group followed by oxidation of the primary alcohol to the acid and removal of the acetate groups using catalytic amounts of sodium methoxide gave the glucuronic acid. Reaction with allyl bromide using resin-bound fluoride gave the title compound. Copyright .COPYRGT. 2011 John Wiley & Sons, Ltd. The synthesis of allyl-[13C6]-glucuronate from .alpha.-D-[13C6]-glucose in five steps is described.
  • Author:
    Manosroi A; Khositsuntiwong N; Komno Ch; Manosoi J; Werner RG; Manosroi W
    Title:
    Chemical stability and cytotoxicity of human insulin loaded in cationic DPPC/CTA/DDAB liposomes.
    Source:
    J Biomed Nanotechnol 7 (2), 308-316 (2011)
    Abstract:
    Liposomes were prepared from DPPC (dipalmitoyl phosphatidyl choline) mixed with Chol (cholesterol) and CTA [cholest-5-en-3-ol(3 beta)(trimethylammonio) acetate] or DDAB (dioctadecyl dimethyl ammonium bromide) at various molar ratios by chloroform film method with sonication. The most physical stable (no sedimentation with an average zeta potential value of 47.7 +/- 1.44 mV) liposomal formulation (DPPC/CTA/DDAB at 7:2:1 molar ratio) was selected to load with human insulin (0.45 mg/mL) by the freeze dried empty liposomes (FDELs) method with the entrapment efficiency of human insulin of 62.72% (determined by gel filtration). Liposomes were spherical shape with unilamellar structure and an average size of 2.26 +/- 0.87 mu m determined by TEM. The percentages of insulin remaining in liposomes when stored at 4 +/- 2, 30 +/- 2 and 45 +/- 2 degrees C for 4 months were 26.21, 36.86 and 15.75% which were higher than human insulin solution of 6.13, 11.31 and 2.61 times, respectively. The percentages of entrapment of human insulin were 62.72 at initial and at 31.72, 64.10 and 8.10 when kept at 4 +/- 2, 30 +/- 2 and 45 +/- 2 degrees C, respectively, for 4 months. The synthesized cationic lipid, CTA, and the DPPC/Chol/CTA liposomes loaded with human insulin demonstrated no cytotoxicity on normal human skin fibroblast but some cytotoxic effects on mouth epidermal cancer cell line. This study has demonstrated the enhancement of chemical stability of human insulin with no cytotoxicity when loaded this protein in cationic DPPC/CTA/DDAB liposomes. The results indicated the potential application of this cationic liposomal formulation for topical therapeutic use.
  • Author:
    Tautermann ChS; Pautsch A
    Title:
    The implication of the first agonist bound activated GPCR X-ray structure on GPCR in silico modeling.
    Source:
    ACS Med Chem Lett 2 (6), 414-418 (2011)
    Abstract:
    The very recently published first X-ray structure of the beta 2 adrenergic receptor in its active state hosting a small molecule (PDB ID: 3P0G) reveals a lot of information about the G-protein-coupled receptor (GPCR) activation process from a structural point of view. When compared to the inactive state crystal structure of beta 2, large differences are seen in the GPCR helical structure at the cytoplasmatic side, whereas very subtle changes occur at the ligand binding site. The observation that there are hardly any differences in the binding site of agonists and inverse agonists implies that in silico predictions of the efficacy of ligands will be very hard. This is illustrated by the example of an already published binding mode of a beta 2 agonist, which has been modeled into the inactive state X-ray structure of the beta 2 receptor. When comparing the modeled structure to the new activated X-ray structure, quantitative agreement of the binding mode is found, implying that the subtle changes between agonist binding to the activated state and inverse agonist binding to the inactive state can currently not be captured by standard in silico modeling methods.
  • Author:
    Malle E; Zhou H; Neuhold J; Spitzenberger B; Klepsch F; Pollak Th; Bergner O; Ecker GF; Stolt-Bergner PC
    Title:
    Random mutagenesis of the Prokaryotic peptide transporter YdgR identifies potential periplasmic gating residues.
    Source:
    J Biol Chem 286 (26), 23121-23131 (2011)
    Abstract:
    The peptide transporter (PTR) family represents a group of proton-coupled secondary transporters responsible for bulk uptake of amino acids in the form of di- and tripeptides, an essential process employed across species ranging from bacteria to humans. To identify amino acids critical for peptide transport in a prokaryotic PTR member, we have screened a library of mutants of the Escherichia coli peptide transporter YdgR using a high-throughput substrate uptake assay. We have identified 35 single point mutations that result in a full or partial loss of transport activity. Additional analysis, including homology modeling based on the crystal structure of the Shewanella oneidensis peptide transporter PepT(so), identifies Glu(56) and Arg(305) as potential periplasmic gating residues. In addition to providing new insights into transport by members of the PTR family, these mutants provide valuable tools for further study of the mechanism of peptide transport.
  • Author:
    Zindell R; Walker ER; Scott J; Amouzgeh P; Wu LF; Ermann M; Thomson D; Fisher MB; Fullenwider CL; Grbic H; Kaplita P; Linehan B; Patel M; Lobbe S; Block S; Albrecht C; Gemkow MJ; Shih DT; Riether D
    Title:
    Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: Optimization of drug-like properties and target independent parameters.
    Source:
    Bioorg Med Chem Lett 21 (14), 4276-4280 (2011)
    Abstract:
    A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability - DERWENT Abstract - New aryl 1,4-diazepanes (1-24) were prepared and tested for in-vitro as CB2 agonists. From initial high throughput screen hit, modifications to each side of core were well tolerated and had CB2 potency, and selectivity profiles could deliver desirable biological profiles. Aqueous solubility and permeability were built into molecules by tetrahydropyran moiety and amide bond bioisosteres, respectively. 5-tert-Butyl 2-[4-(3-chloro 5-trifluoromethyl pyridin-2-yl) [1,4]diazepan-1-yl] benzooxazole (7) was the most active compound showing excellent CB2 cAMP potency and efficacy, however, it showed low selectivity over CB1 and aqueous solubility. On the other hand, [4-(5-tert-butyl benzooxazol-2-yl) [1,4]diazepan-1-yl] (tetrahydro-pyran-4-yl) methanone (17), also potent CB2 agonist, displayed little change to CB2 potency but greatly enhanced selectivity profile with improved aqueous solubility. In cellular assay using CHO cells, 4-(3-chloro 5-trifluoromethyl pyridin-2-yl) [1,4]diazepane-1-carboxylic acid (3,4-dichloro-phenyl)-amide (1), identified from high throughput screen, had CB2 cAMP EC50 of 154 nM with 92% efficacy and greater than 130-fold selectivity over CB1. Replacement of 3,4-dichlorophenyl residue with 3-tert-butyl-5-aminoisoxazole in 1,4-diazepane analog (2) resulted in 30-fold improvement in potency (CB2 EC50: 5 nM, efficacy: 106%) and decrease in selectivity (80). Isoxazole analog (15) was 1 of the best compounds described in amide/urea type of molecules with CB2 EC50 of 67 nM and efficacy of 104% (selectivity: 104). Replacement of aromatic with small cycloalkyl substituent linked to diazepane core via amide bond shown in cyclopentyl-propan-2-one analog (16) (CB2 EC50: 2 nM, efficacy: 100%, selectivity: 60, solubility: 26 ug/ml) offered improvement in solubility and selectivity without much loss in potency as compared to 5-tert-butyl-benzooxazole analog (7) (CB2 EC50: 0.51 nM, efficacy: 107%, selectivity: 33, solubility: 0.1 ug/ml). Expanding upon this cycloalkyl, tetrahydropyran was prepared as benzoxazole analog (17) (CB2 EC50: 1 nM, efficacy: 105%, selectivity: 1770, solubility: above 96 ug/ml). Incorporation of this heteroalkyl offered little change to CB2 potency but greatly enhanced selectivity profile while improving aqueous solubility of molecule. Compound (17) (Caco-2 AB/BA: 49/64 cm/sec x 10 power -6) as compared to (15) (Caco-2 AB/BA: 7/42 cm/sec x 10 power -6) showed improvement in efflux ratio as measured by flux across Caco-2 monolayers. Also, (17) showed high in-vitro human clearance in human liver microsomes (above 75% QH).
  • Author:
    Haddad N; Qu B; Rodriguez S; van der Veen S; Reeves DC; Gonnella NC; Lee H; Grinberg N; Ma S; Krishnamurthy D; Wunberg T; Senanayake CH
    Title:
    Catalytic asymmetric hydrogenation of heterocyclic ketone-derived hydrazones pronounced solvent effect on the inversion of configuration.
    Source:
    Tetrahedron Lett 52 (29), 3718-3722 (2011)
    Abstract:
    An enantioselective hydrogenation of hydrazones derived from heterocyclic ketones was developed with up to 85% ee. The enantiomeric purity was enriched to >99% ee by crystallization from EtOAc in >80% yield. Optimization studies have revealed a notable solvent effect that resulted in inversion of enantioselectivity from 85% ee in MeOH to -27% ee in DCE. The hydrazone geometry and possible hydrogenation via endocyclic alkene were examined as possible factors for the inversion of enantioselectivity.
  • Author:
    Beaulieu PL; Chabot C; Duan J; Garneau M; Gillard J; Jolicoeur E; Poirier M; Poupart M-A; Stammers TA; Kukolj G; Tsantrizos YS
    Title:
    Indole 5-carboxamide thumb pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): Central amino acid linker and right-hand-side SAR studies.
    Source:
    Bioorg Med Chem Lett 21 (12), 3664-3670 (2011)
    Abstract:
    In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC50 &lt;100 nM), physicochemical properties and ADME characteristics.
  • Author:
    Beaulieu PL; Gillard J; Jolicoeur E; Duan J; Garneau M; Kukolj G; Poupart M-A
    Title:
    From benzimidazole to indole-5-carboxamide thumb pocket I inhibitors of HCV NS5B polymerase. Part 1: Indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons.
    Source:
    Bioorg Med Chem Lett 21 (12), 3658-3563 (2011)
    Abstract:
    Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC50 &lt;100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.
  • Author:
    Wuerthner F; Bach Th; Beifuss U; Karpetyan G; Mueller TJJ; Bielitza M; Pietruszka J; Senge MO; Giernoth R; Ditrich K; von Deyn W; Newton T; Rheinheimer J; Oestereich M; Muniz K; Straub BF; Winkler M; Schreiner PR; Lindel Th; Breinbauer R; Sewald N; Weinhold E; Draeger G; Arenz Ch; Huettel W; Mueller M; Gschwind R; Braese St; Schroeder D; Pfau R; Biskup M
    Title:
    Organic Chemistry 2010.
    Source:
    Nachr Chem 59 (3), 254-283 (2011)
  • Author:
    Tautermann ChS
    Title:
    The use of G-protein coupled receptor models in lead optimization.
    Source:
    Future Med Chem 3 (6), 709-721 (2011)
    Abstract:
    With the emerging new crystal structures of G-protein coupled receptors (GPCRs), the number of reported in silico receptor models vastly increases every year. The use of these models in lead optimization (LO) is investigated here. Although there are many studies where GPCR models are used to identify new chemotypes by virtual screening, the classical application in LO is rarely reported. The reason for this may be that the quality of a model, which is appropriate for atomistic modeling, must be very high, and the biology of GPCR ligand-dependent signaling is still not fully understood. However, the few reported studies show that GPCR models can be used efficiently in LO for various problems, such as affinity optimization or tuning of physicochemical parameters.
  • Author:
    Proudfoot J; Nosjean O; Blanchard J; Wang J; Besson D; Crankshow D; Gauglitz G; Hertzberg R; Homon C; Llewellyn L; Neubig R; Walker L; Villa P
    Title:
    Glossary of terms used in biomolecular screening (IUPAC recommendations 2011).
    Source:
    Pure Appl Chem 83 (5), 1129-1158 (2011)
    Abstract:
    Biomolecular screening is now a crucial component of the drug discovery process, and this glossary will be of use to practitioners in the field of screening and to those who interact with the screening community. The glossary contains definitions related to various aspects of the screening process such as assay types, data handling, and relevant technologies. Many of the terms used in this discipline are not covered by existing glossaries, and where they are, the definitions are often not appropriate for this field. Where appropriate, this document provides new or modified definitions to better reflect the new context. The field of biomolecular screening is multidisciplinary in nature, and this glossary, containing authoritative definitions, will be useful not only for regular practitioners, but also for those who make use of data generated during the screening process.
  • Author:
    Reeves DC; Rodriguez S; Lee H; Haddad N; Krishnamurthy Dh; Senanayake ChH
    Title:
    Palladium catalyzed alkoxy- and aminocarbonylation of vinyl tosylates.
    Source:
    Org Lett 13 (9), 2495-2497 (2011)
    Abstract:
    The palladium catalyzed alkoxycarbonylation and aminocarbonylation of vinyl tosylates are described. A variety of ketone and aldehyde derived vinyl tosylates may be carbonylated in the presence of primary, secondary, and tertiary alcohols, or primary and secondary amines, to provide the corresponding esters and amides in good yields. The alkoxycarbonylation was applied to a short synthesis of isoguvacine.
  • Author:
    Koecher Th; Swart R; Mechtler K
    Title:
    Ultra-high-pressure RPLC hyphenated to an LTQ-orbitrap velos reveals a linear relation between peak capacity and number of identified peptides.
    Source:
    Anal Chem 83 (7), 2699-2704 (2011)
    Abstract:
    Currently, unbiased protein identification is mostly performed by directly coupling reversed-phase liquid chromatography (RPLC) via electrospray ionization to a mass spectrometer. In contrast to the innovations in mass spectrometric instrumentation, cutting-edge technology in RPLC has generally not been well adopted. Here, we describe the effects of increased peak capacities on the number of identified proteins and peptides in complex mixtures utilizing collision-induced dissociation on an LTQ-Orbitrap Velos, providing a rationale for using advanced RPLC technology in LC-MS/MS. Using two different column lengths and gradient times between 1 and 10 h, we found a linear relation between the obtained peak capacities and the number of identified peptides. We identified on average 2516 proteins in the tryptic digest of 1 mu g of HeLa lysate using an 8 h gradient on a 50 cm column packed with 2 mu m C18 reversed-phase chromatographic. material.
  • Author:
    Wallnoefer HG; Liedl KR; Fox Th
    Title:
    A challenging system: Free energy prediction for factor Xa.
    Source:
    J Comput Chem 32 (8), 1743-1752 (2011)
    Abstract:
    Factor Xa (fXa) is a promising target for antithrombotic drugs. Recently, we presented a molecular dynamics study on fXa, which highlighted the need for a careful system setup to obtain stable simulations. Here, we show that these simulations can be used to predict the free energy of binding of several fXa inhibitors. We tested molecular mechanics/Poisson-Boltzmann surface area, molecular mechanics/Generalized Born surface area, and linear interaction energy (LIE) on a small data set of fXa ligands. The continuum solvent approaches only yield satisfying correlations to the experimental results if some of the water molecules are explicitly included in the free energy calculations. LIE gave reasonable results if a sufficiently large data set is used. In general, our procedure of setting up the fXa simulation system enabled MD simulations, which produce adequate ensembles for free energy calculations.
  • Author:
    Frutos RP; Tampone P; Mulder JA; Xu Y; Reeves D; Wang X-J; Zhang L; Krishnamurthy D; Senanayake CH
    Title:
    A new and practical boronic acid catalyzed intramolecular cyclodehydration of ureas for the synthesis of LFA-1 antagonists.
    Source:
    Tetrahedron Lett 52 (19), 2465-2467 (2011)
    Abstract:
    A streamlined and practical approach to 1H-imidazo[1,2-?]imidazol-2-one LFA-1 antagonist (1) that features as the key step a novel intramolecular boronic acid catalyzed cyclocondensation of a urea and an amide is reported.
  • Author:
    Rodriguez S; Qu B; Haddad N; Reeves DC; Tang W; Lee H; Krishnamurthy Dh; Senanayake ChH
    Title:
    Oxaphosphole-based monophosphorus ligands for palladium-catalyzed amination reactions.
    Source:
    Adv Synth Catal 353 (4), 533-537 (2011)
    Abstract:
    A novel class of C-2-substituted oxaphosphole-based monophosphines 1-4 has been synthesized. Palladium complexes derived from these ligands and their C-2-unsubstituted analogs provide general catalysts for amination reactions of challenging aryl and heteroaryl halides with sterically hindered anilines and alkylamines.
  • Author:
    Tang W; Keshipeddy S; Zhang Y; Wei X; Savoie J; Patel ND; Yee NK; Senanayake ChH
    Title:
    Efficient monophosphorus ligands for palladium-catalyzed miyaura borylation.
    Source:
    Org Lett 13 (6), 1366-1369 (2011)
    Abstract:
    In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings.
  • Author:
    Herdemann M; Weber A; Jonveaux J; Schwoebel F; Stoeck M; Heit I
    Title:
    Optimisation of ITK inhibitors through successive iterative design cycles.
    Source:
    Bioorg Med Chem Lett 21 (6), 1852-1856 (2011)
    Abstract:
    Based on a hit cluster of compounds inhibiting interleukin-2 inducible T-cell kinase (ITK) in the submicromolar range a series of ITK inhibitor libraries were synthesized. Through iterative design cycles including kinase crystal structure information, indolylindazole libraries were identified which showed low nanomolar activity in enzymatic and cellular assays. The potential of these novel lead series was confirmed through in vivo tests in an anti-CD3-IL2 mouse model. The intravenous administration of highly potent ITK inhibitor 11o resulted in dose-dependent, efficient suppression of IL-2. - DERWENT Abstract - Based on a hit cluster of compounds inhibiting IL-2 inducible T-cell kinase (ITK) in the submicromolar range, a series of ITK inhibitor libraries was synthesized. Through iterative design cycles including kinase crystal structure information, indolylindazole libraries were identified which showed low nanomolar activity in enzymatic and cellular assays. The potential of these novel lead series was confirmed through in-vivo tests in an anti-CD3-IL-2 mouse model. I.v. 3-(6-methyl 1H-indol-2-yl) N-(pyrrolidin-3-yl) 1H-indazol-5-amine (11o), a highly potent ITK inhibitor, resulted in dose-dependent, efficient suppression of IL-2. I.v. and p.o. treatment with (11o) was well-tolerated at all dose levels and no obvious side effects were observed compared to the positive control group. 2-(Dimethylamino) N-[3-(6-methyl 1H-indol-2-yl) 1H-indazol-5-yl] acetamide (8c) and 2-methoxy N-[3-(6-methoxy 1H-indol-2-yl) 1H-indazol-5-yl] acetamide (8o) showed ITK IC50 values of 0.065 and 0.098 uM in enzyme assay and 0.6 and 0.5 uM in cell assay, respectively. Small substituents were tolerated at position-6 of the indazole, but compounds with larger substituents were inactive. N-[3-(6-Methyl 1H-indol-2-yl) 1H-indazol-5-yl] methanesulfonamide (9a) and its (1-methyl 1H-imidazol 4-yl)sulfonamide analog (9i) showed ITK IC50 values of 0.036 and 0.026 uM in enzyme assay and 0.4 and 0.4 uM in cell assay, respectively. 3-(6-Methyl 1H-indol-2-yl) N-(piperidin-4-yl) 1H-indazol-5-amine (11h) and its N-(N-benzylpiperidin 4-yl) analog (11k) and compound (11o) had IC50 of 0.016, 0.023, and 0.08 uM in enzyme assay and 0.09, 0.50, and 0.02 uM in cell assay, respectively. Compounds (11k and 11o) (IC50=0.023 and 0.08 uM in enzyme assay and 0.50 and 0.02 uM in cell assay, respectively) showed a medium selectivity inhibiting about 20 further kinases in a similar range as ITK. All compounds inhibited Aurora A, Flt3, JAK2, Ret, and TrkA equipotently with regard to ITK. In-vivo, i.v. single administration of (11o) resulted in a dose-dependent IL-2 suppression in an anti-CD3 Ab-induced IL-2 mouse model. I.v. dose of 10 mg/kg resulted in IL-2 concentration levels below the detection limit. The ED50 of IL-2 inhibition was calculated to be 2.1 mg/kg. Moreover, after p.o. administration of 10 mg/kg of (11o), the measured IL-2 inhibition was above 80% compared to the vehicle.
  • Author:
    Skylaris Ch-K; Fox St; Pittock Ch; Essex J; Fox Th; Tautermann Ch; Malcolm N
    Title:
    Free energies of binding from large scale density functional theory.
    Source:
    ACS March Meeting, Anaheim (United States), Mar 27-31, 2011. Abstr Pap Am Chem Soc 241 MA 50-COMP (2011)
  • Author:
    Laplante SR; Edwards PJ; Fader LD; Jakalian A; Hucke O
    Title:
    Revealing atropisomer axial chirality in drug discovery.
    Source:
    ChemMedChem 6 (3), 505-513 (2011)
    Abstract:
    An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20kcalmol-1 was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.
  • Author:
    Riether D; Wu L; Cirillo PF; Berry A; Walker ER; Ermann M; Noya-Marino B; Jenkins JE; Albaugh D; Albrecht C; Fisher M; Gemkow MJ; Grbic H; Loebbe S; Moeller C; O'Shea K; Sauer A; Shih D-T; Thomson DS
    Title:
    1,4-diazepane compounds as potent and selective CB2 agonists. Optimization of metabolic stability.
    Source:
    Bioorg Med Chem Lett 21 (7), 2011-2016 (2011)
    Abstract:
    A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified. - DERWENT Abstract - A high-throughput screening campaign identified 1,4-diazepane compounds which were potent Cannabinoid receptor 2 (CB2) agonists with excellent selectivity against the Cannabinoid receptor 1 (CB1). Starting from the initial hit N-(4-butylphenyl) 4-(3-cyclopentylpropanoyl) 1,4-diazepane 1-carboxamide (1), SAR focused on evaluating the phenyl substituents (compounds (2-6)), aliphatic and aromatic amide groups (compounds (7-16)), heteroaromatic urea substituents R2 (compounds (17-27)), and amide groups R1 (compounds (28-43)). This series of compounds suffered from low metabolic stability in-vitro. Following various strategies, compounds with a good stability in liver microsomes and rat pharmacokinetic (PK) profile at p.o. and i.v. dose in-vivo were identified, e.g. (N-(5-tert-butyl 1,2-oxazol-3-yl) 4-[(oxan-4-yl) carbonyl] 1,4-diazepane 1-carboxamide (17). In a CB2 functional cellular assay measuring the cAMP production in forskolin (colforsin)-stimulated CHO cells transfected with the human CB2 receptor, (1) was a partial agonist for CB2 (EC50=136 nM; 67% efficacy). Compound (1) did not activate the CB1 receptor up to 20 uM. When incubated with human liver microsomes (HLM) in-vitro, (1) showed a short half-life of 5 min and low solubility of 3 ug/ml at pH 7.4. Isoxazole isomers (17 and 18) showed a 2- and 4-fold increase in CB2 potency, respectively, compared to the phenyl analog (16), while maintaining a high selectivity (CB2 EC50=67 and 26 vs. 111 nM, respectively; CB1 EC50 over 20000 nM). The in-vitro half-life of (17 and 18) was improved to over 120 min (vs. 11 min for (16)). The morpholino and thiomorpholino urea analogs (39 and 40) showed comparable potency and selectivity to morpholinomethyl and dioxothiomorpholinomethyl amides (37 and 38) (CB2 EC50=177 and 135 vs. 157 and 107 nM, respectively; CB1 EC50 over 20000 nM), with improved HLM half-life (58 and over 120 vs. 35 and 38 min, respectively). Due to their superior profile, (17, 18, 38, and 40) were tested in various in-vitro assays. The solubility of amides (17, 18, and 38) was more favorable than that of urea (40) (over 37 to over 96 vs. 18 ug/ml at pH 7.4). Compounds (17, 38, and 40) showed a clean profile in the CYP inhibition assay against various isoforms (IC50 over 30 uM) and also showed no hERG inhibition when tested at 1 uM in a Patch Express assay. PK profile of (17) was tested in Wistar rat at i.v. 1 umol/kg and p.o. 10 umol/kg in-vivo, showing a low Vd (0.87 l/kg) and medium clearance (34 ml/min/kg), with p.o. bioavailability of 28%.
  • Author:
    Mangette JE; Chen X; Krishnamoorthy R; Samuel Vellekoop A; Csakai AJ; Camara F; Paquette WD; Wang H-J; Takahashi H; Fleck R; Roth GP
    Title:
    2-Trifluoroacetyl aminoindoles as useful intermediates for the preparation of 2-acylamino indoles.
    Source:
    Tetrahedron Lett 52 (12), 1292-1295 (2011)
    Abstract:
    A three-step method was developed to convert N-1 unprotected 3-substituted indoles to 3-substituted 2-acylaminoindoles. Established indole chlorination chemistry was employed to generate stable 2-trifluoroacetylamino indoles, which were subsequently deprotected and selectively acylated.
  • Author:
    Zheng J-C; Yun SY; Sun C; Lee N-K; Lee D
    Title:
    Selectivity control in alkylidene carbene-mediated C-H insertion and allene formation.
    Source:
    J Org Chem 76 (4), 1086-1099 (2011)
    Abstract:
    Regioselectivity of alkylidene carbene-mediated C-H insertion was explored utilizing electronic, conformational, steric, and stereoelectronic effects. Relying on these factors, highly regio-and chemoselective carbene insertion reaction of C-H bonds in different environments could be obtained. The observed selectivity clearly indicates that an electronic effect plays a more important role than steric effect. In general, C-H bonds in conformationally rigid cyclic environments are less reactive than those in acyclic systems toward carbene insertion, and in this situation, a competing intermolecular reaction between alkylidene carbene and trimethylsilyldiazomethane led to the formation of allenylsilanes. The formation of allenylsilane becomes more favorable as the concentration of reaction becomes higher, as well as the C-H bonds undergoing insertion becomes electronically and conformationally deactivated.
  • Author:
    qqEdwards PJ
    Title:
    The design and synthesis of libraries for the discovery of antibacterial and antifungal substances.
    Source:
    Drug Discov Today 16 (5-6), 278-279 (2011)
  • Author:
    Burger StK; Thompson DC; Ayes PW
    Title:
    Quantum mechanics/molecular mechanics strategies for docking pose refinement: Distinguishing between binders and decoys in cytochrome c peroxidase.
    Source:
    J Chem Inform Modeling 51 (1), 93-101 (2011)
    Abstract:
    We investigate the effect of systematically applying molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) to docked poses in an attempt to improve the correspondence between theoretical prediction and experimental observation. The proposed scheme involves running a short time scale MD simulation on a docked ligand pose (and any known structurally important crystal structure waters in the active site), followed by QM/MM minimization. Both of these steps are relatively fast for moderately sized ligands; longer time scale MD involving the protein is not found to improve the results. The final binding energy is given in terms of the QM/MM total energy, a van der Waals correction, and a term to account for desolvation effects. This methodology is first tested with a trypsin inhibitor, for which we establish the importance of running MD before reoptimizing with QM/MM. The method is then applied to cytochrome c peroxidase using a set of binders and decoys. In this example, the proposed methodology affords much better discrimination between binders and decoys than the traditional docking approach used. For both systems presented, application of this protocol results in a significantly better energetic ranking and a smaller root mean squared deviation from known crystallographic ligand poses. This work highlights the importance of including polarization effects through QM/MM and of sampling with MD to refine a set of initial docked poses.
  • Author:
    Jallo LJ; Chen Y; Bowen J; Etzler F; Dave R
    Title:
    Prediction of inter-particle adhesion force from surface energy and surface roughness.
    Source:
    J Adhes Sci Technol 25 (4-5), 367-384 (2011)
    Abstract:
    Fine powder flow is a topic of great interest to industry, in particular for the pharmaceutical industry; a major concern being their poor flow behavior due to high cohesion. In this study, cohesion reduction, produced via surface modification, at the particle scale as well as bulk scale is addressed. The adhesion force model of Derjaguin-Muller-Toporov (DMT) was utilized to quantify the inter-particle adhesion force of both pure and surface modified fine aluminum powders (?8 ?m in size). Inverse Gas Chromatography (IGC) was utilized for the determination of surface energy of the samples, and Atomic Force Microscopy (AFM) was utilized to evaluate surface roughness of the powders. Surface modification of the original aluminum powders was done for the purpose of reduction in cohesiveness and improvement in flowability, employing either silane surface treatment or dry mechanical coating of nano-particles on the surface of original powders. For selected samples, the AFM was utilized for direct evaluation of the particle pull-off force. The results indicated that surface modification reduced the surface energy and altered the surface nano-roughness, resulting in drastic reduction of the inter-particle adhesion force. The particle bond number values were computed based on either the inter-particle adhesion force from the DMT model or the inter-particle pull-off force obtained from direct AFM measurements. Surface modification resulted in two to three fold reductions in the Bond number. In order to examine the influence of the particle scale property such as the Bond number on the bulk-scale flow characterization, Angle of Repose (AOR) measurements were done and showed good qualitative agreements with the Bond number and acid/base surface characteristics of the powders. The results indicate a promising method that may be used to predict flow behavior of original (cohesive) and surface modified (previously cohesive) powders utilizing very small samples, and that the surface modification can drastically improve the powder flow for industrially relevant materials.
  • Author:
    Ye P; Kuhn C; Juan M; Sharma R; Connolly B; Alton G; Liu H; Stanton R; Kablaoui NM
    Title:
    Potent and selective thiophene urea-templated inhibitors of S6K.
    Source:
    Bioorg Med Chem Lett 21 (2), 849-852 (2011)
    Abstract:
    S6K1 (p70 S6 kinase-1) is thought to play a critical role in the development of obesity and insulin resistance, thus making it an attractive target in developing medicines for the treatment of these disorders. We describe a novel thiophene urea class of S6K inhibitors. The lead matter for the development of these inhibitors came from mining the literature for reports of weak off-target S6K activity. These optimized inhibitors exhibit good potency and excellent selectivity for S6K over a panel of 43 kinases. .COPYRGT. 2010 Elsevier Ltd. All rights reserved.
  • Author:
    Tye H; Mueller SG; Prestle J; Scheuerer S; Schindler M; Nosse B; Prevost N; Brown CJ; Heifetz A; Moeller C; Pedret-Dunn A; Wittaker M
    Title:
    Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders.
    Source:
    Bioorg Med Chem Lett 21 (1), 34-37 (2011)
    Abstract:
    The discovery of a novel series of 5-HT2C agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.
  • Author:
    Fader LD; Bethell R; Bonneau P; Boes M; Bousquet Y; Cordingley MG; Coulombe R; Deroy P; Faucher A-M; Gagnon A; Goudreau N; Grand-Maitre C; Guse I; Hucke O; Kawai SH; Lacoste J-E; Landry S; Lemke CT; Malenfant E; Mason S; Morin S; O'Meara J; Simoneau B; Titolo S; Yoakim C
    Title:
    Discovery of a 1,5-dihydrobenzo[b][1.4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly.
    Source:
    Bioorg Med Chem Lett 21 (1), 398-404 (2011)
    Abstract:
    The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity. - DERWENT Abstract - The discovery of a 1,5-dihydrobenzo [b][1,4]diazepine 2,4-dione series (6-20, 30-43, 45-48) of inhibitors of HIV-1 capsid assembly and viral replication was described, based on the optimization of hit (3E)-3-[(butylamino) methylidene] 8-chloro 1-phenyl 5H-1,5-dihydrobenzo [b][1,4]diazepine 2,4-dione (1). SAR showed that the replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring resulted to compounds that inhibited both capsid assembly and RT. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent identified the lead compound 1-methyl 3,5-diphenyl 7-(trifluoromethyl) 3H-1,5-benzodiazepine 2,4-dione (48), showing similar potency to the original hit compound in the capsid assembly assay, an enhancement in antiviral potency and no inhibition of RT. The enamine functionality was found to be important for potency since the C3 unsubstituted analog (6a) suffered a complete loss of potency in the HIV-1 capsid assembly assay (IC50 over 46 uM). Varying the N5 group from N-H (7) showed that small alkyl groups (methyl (10) and ethyl (11)) were well tolerated, leading to moderate improvements in IC50 value of 2- to 3-fold (IC50=1.4 vs. 0.59 and 0.47 uM, respectively). For the effect of 5-, 6-, 7-and 8-substitution on the benzodiazepine core, lipophilic substituents were well tolerated at all positions of the phenyl ring, but the 7-position was preferred. For the modification of the N1 phenyl group, substitution of the phenyl group with a 2-thiophenyl group led to an equipotent analog (cf. compound (20) to (10), IC50=0.50 vs. 0.59 uM). Replacing the enamine functionality of the hit series with either an imidazole or a pyrazole ring identified compounds that inhibited both capsid assembly and RT. The unsubstituted pyrazole derivative (30a) showed an IC50 value of 0.30 uM in the capsid assembly assay and an EC50 of 7.8 uM in the viral replication assay. The unsubstituted imidazole derivative (30b) was among the most potent analogs tested with IC50 value (0.21 uM) similar to that of unsubstituted pyrazole (30a), but an EC50 value about 2-fold lower (3.8 uM). Further modification of the bicyclic benzodiazepine scaffold identified the phenyl analog (48), with good potency in the antiviral assay, an acceptable window vs. cytotoxicity (IC50=1.2 uM; CC50 over 20 uM) and importantly showed no shift when the wild type and double mutant assay (EC50=3.0/2.7 uM) results were compared.
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