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

ACS Medicinal Chemistry Letters
Mui CheungKevin S Thorneloe

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-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.

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Citations

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Jul 18, 2019·American Journal of Physiology. Renal Physiology·Takamitsu SaigusaDouglas C Eaton
Mar 9, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Daniel M CollierKalev Freeman
Aug 21, 2019·Pflügers Archiv : European journal of physiology·Carolina da Silveira ScarpelliniKênia Cardoso Bícego
Sep 26, 2020·Frontiers in Cell and Developmental Biology·Sina C RosenkranzManuel A Friese
Apr 19, 2018·Journal of Neurophysiology·John N BarrettSuhrud M Rajguru
Oct 12, 2018·Pharmaceuticals·Zili Xie, Hongzhen Hu
Jan 1, 2020·American Journal of Physiology. Cell Physiology·Yaqiu LiLinda J Lowe-Krentz
Mar 22, 2019·International Journal of Molecular Sciences·Erik J Behringer, Md A Hakim
Sep 7, 2020·Annals of the New York Academy of Sciences·Satyanarayana Achanta, Sven-Eric Jordt
Sep 23, 2020·British Journal of Pharmacology·Pablo Doñate-MacianMiguel A Valverde
Feb 18, 2020·Bioorganic & Medicinal Chemistry Letters·Brian G LawhornDavid J Behm
Apr 22, 2021·Proceedings of the National Academy of Sciences of the United States of America·Zdravka DanevaSwapnil K Sonkusare
Jun 3, 2021·International Journal of Molecular Sciences·Kazunori Watanabe, Takashi Ohtsuki
Jul 11, 2021·Science Advances·Christopher L YankaskasKonstantinos Konstantopoulos
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