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

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.

Keywords: GSK2193874; L-type channel inhibition; TRPV4; TRPV4 antagonist; TRPV4 inhibitor; congestive heart failure.

Figure 1

Structures of TRPV4 antagonists.

Figure 2

Quinoline hit 1a and chemistry strategies focused on R₁–R₄ optimization.

Scheme 1. General Synthesis of Quinoline Derivatives

Reagents and conditions: (a) KOH, H₂O/EtOH; (b) 2-oxobutanoic acid, EtOH; (c) (COCl)₂, DMF, CH₂Cl₂, then MeOH; (d) benzoyl peroxide, NBS, CCl₄; (e) R₂-substituted piperidine, CH₃CN; (f) KOH, MeOH/H₂O; (g) R₃,R_3a-substituted benzylamine, T₃P, i-Pr₂NEt, CH₂Cl₂.