Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)

被引：34

作者：

Brooks, Carl A. ^{[1
]}

Barton, Linda S. ^{[1
]}

Behm, David J. ^{[1
]}

Eidam, Hilary S. ^{[1
]}

Fox, Ryan M. ^{[1
]}

Hammond, Marlys ^{[1
]}

Hoang, Tram H. ^{[1
]}

Holt, Dennis A. ^{[1
]}

Hilfiker, Mark A. ^{[1
]}

Lawhorn, Brian G. ^{[1
]}

Patterson, Jaclyn R. ^{[1
]}

Stoy, Patrick ^{[1
]}

Roethke, Theresa J. ^{[1
]}

Ye, Guosen ^{[1
]}

Zhao, Steve ^{[1
]}

Thorneloe, Kevin S. ^{[1
]}

Goodman, Krista B. ^{[1
]}

Cheung, Mui ^{[1
]}

机构：

[1] GlaxoSmithKline, Heart Failure Discovery Performance Unit, Metab Pathways & Cardiovasc Therapeut Area, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 08期

关键词：

GSK2798745; TRPV4; congestive heart failure; conformational bias; volume of distribution; INTRAVENOUS PHARMACOKINETIC PARAMETERS; QUALITATIVE EVALUATION; CATION CHANNEL; ACTIVATION; IDENTIFICATION; EXTRAPOLATION; PROTEIN; HUMANS; MONKEY; SERIES;

D O I：

10.1021/acsmedchemlett.9b00274

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

引用

页码：1228 / 1233

页数：11

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