Identification of orally-bioavailable antagonists of the TRPV4 ion-channel. Issue 18 (15th September 2015)

• Record Type: Journal Article
• Authors: Wei, Zhi-Liang; Nguyen, Margaret T.; O'Mahony, Donogh J.R.; Acevedo, Alejandra; Zipfel, Sheila; Zhang, Qingling; Liu, Luna; Dourado, Michelle; Chi, Candace; Yip, Victor; DeFalco, Jeff; Gustafson, Amy; Emerling, Daniel E.; Kelly, Michael G.; Kincaid, John; Vincent, Fabien; Duncton, Matthew A.J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 18(2015)
• Page Start: 4011
• Page End: 4015
• Publication Date: 2015-09-15
• Subjects: TRPV4 -- Antagonist -- RN-9893 -- RN-1734 -- Pain; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.06.098
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Antagonists of the TRPV4 receptor were identified using a focused screen, followed by a limited optimization program. The leading compounds obtained from this exercise, RN-166523 and RN-989326, showed moderate oral bioavailability when dosed to rats. The lead molecule, RN-989326, inhibited human, rat and murine variants of TRPV4, and showed excellent selectivity over related TRP receptors, such as TRPV1, TRPV3 and TRPM8. The overall profile for RN-9893 may permit its use as a proof-of-concept probe for in vivo applications.