Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

Harrison Lee A.; Atkinson Stephen J.; Bassil AnnaChung Chun-waGrandi PaolaGray James R. J.Levernier EtienneLewis AntoniaLugo DavidMessenger CassieMichon Anne-MarieMitchell Darren J.Preston AlexPrinjha Rab K.Rioja InmaculadaSeal Jonathan T.Taylor SimonWall Ian D.Watson Robert J.Woolven James M.Demont Emmanuel H.

首页> 外文期刊>Journal of Medicinal Chemistry >Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

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Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

机译：Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

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Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.

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《Journal of Medicinal Chemistry》 |2021年第15期|10742-10771|共30页
作者
Harrison Lee A.; Atkinson Stephen J.; Bassil AnnaChung Chun-waGrandi PaolaGray James R. J.Levernier EtienneLewis AntoniaLugo DavidMessenger CassieMichon Anne-MarieMitchell Darren J.Preston AlexPrinjha Rab K.Rioja InmaculadaSeal Jonathan T.Taylor SimonWall Ian D.Watson Robert J.Woolven James M.Demont Emmanuel H.;
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GlaxoSmithKline, Epigenet Discovery Performance Unit, Stevenage SG1 2NY, Herts, England;

GlaxoSmithKline, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England;

GlaxoSmithKline, Immunoinflammat Therapy Area Unit, Quantitat Pharmacol, Stevenage SG1 2NY, Herts, EnglandGlaxoSmithKline, Platform Technol & Sci, IVIVT Cellzome, D-69117 Heidelberg, Germany;

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Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

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