瞬时受体电位通道
TRPV4型
效力
药理学
水肿
体内
药代动力学
化学
医学
受体
内科学
生物化学
体外
生物
生物技术
作者
Carl Brooks,Linda S. Barton,David J. Behm,Hilary S. Eidam,Ryan M. Fox,Marlys Hammond,Tram Hoang,Dennis A. Holt,Mark A. Hilfiker,Brian G. Lawhorn,Jaclyn R. Patterson,Patrick Stoy,Theresa J. Roethke,Guosen Ye,Steve Zhao,Kevin S. Thorneloe,Krista B. Goodman,Mui Cheung
标识
DOI:10.1021/acsmedchemlett.9b00274
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.
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