Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors

被引：19

作者：

Lucas, Simon C. C. ^{[2
]}

Atkinson, Stephen J. ^{[2
]}

Chung, Chun-Wa ^{[1
]}

Davis, Rob ^{[2
]}

Gordon, Laurie ^{[1
]}

Grandi, Paola ^{[3
]}

Gray, James J. R. ^{[4
]}

Grimes, Thomas ^{[2
,5
]}

Phillipou, Alexander ^{[1
]}

Preston, Alex G. ^{[2
]}

Prinjha, Rab K. ^{[2
]}

Rioja, Inmaculada ^{[2
]}

Taylor, Simon ^{[4
,6
]}

Tomkinson, Nicholas C. O. ^{[7
]}

Wall, Ian ^{[1
]}

Watson, Robert J. ^{[2
]}

Woolven, James ^{[1
]}

Demont, Emmanuel H. ^{[2
]}

机构：

[1] GlaxoSmithKline, Med Res Ctr, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline, Med Res Ctr, Epigenet Discovery Performance Unit, Stevenage SG1 2NY, Herts, England

[3] IVIVT Cellzome, Platform Technol & Sci, D-69117 Heidelberg, Germany

[4] GlaxoSmithKline, Med Res Ctr, Immunoinflammat Therapy Area Unit, Quantitat Pharmacol, Stevenage SG1 2NY, Herts, England

[5] Alzheimers Res UK, Oxford Drug Discovery Inst, Oxford, England

[6] Pharmaron, Drug Discovery Serv Europe, Hertford Rd, Hoddesdon EN11 9BU, England

[7] Univ Strathclyde, Dept Pure & Appl Chem, WestCHEM, Glasgow G1 1XL, Lanark, Scotland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 15期

基金：

英国工程与自然科学研究理事会;

关键词：

HOLE APPROACH; SELECTIVE-INHIBITION; INFLAMMATION; PROTEIN; BRD4; SOLUBILITY; DISCOVERY; SEQUENCE; TARGET; MODELS;

D O I：

10.1021/acs.jmedchem.1c00344

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000- fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

引用

页码：10711 / 10741

页数：31

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