Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema

详细信息    查看全文

• 作者：Mark A. Hilfiker ; Tram H. Hoang ; Johan Cornil ; Hilary S. Eidam ; Daniel S. Matasic ; Theresa J. Roethke ; Michael Klein ; Kevin S. Thorneloe ; Mui Cheung
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：4
• 期：2
• 页码：293-296
• 全文大小：258K
• 年卷期：v.4,no.2(February 14, 2013)
• ISSN：1948-5875

文摘

High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.

Keywords:

ion channel; calcium channel; vanilloid receptor; transient receptor potential; TRPV4; heart failure; pulmonary edema; benzimidazole