Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2017 May 20

PMID 28523109

Citations 44

Authors

Mui Cheung

Weike Bao

David J Behm

Carl A Brooks

Michael J Bury

Sarah E Dowdell

Hilary S Eidam

Ryan M Fox

Krista B Goodman

Dennis A Holt

Dennis Lee

Theresa J Roethke

Robert N Willette

Xiaoping Xu

Guosen Ye

Kevin S Thorneloe

Affiliations

Soon will be listed here.

Abstract

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo--(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, ) after addressing an unexpected off-target cardiovascular liability observed from studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both and .

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