Discovery of a novel orally active TRPV4 inhibitor: Part 1. Optimization from an HTS hit

Sami, Yuichi; Morita, Masataka; Kubota, Hirokazu; Hirabayashi, Ryoji; Seo, Ryushi; Nakagawa, N.

doi:10.1016/j.bmc.2019.05.041

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…As part of a longstanding program aimed at identifying agents for the treatment of heart failure and respiratory diseases, we and others have developed potent TRPV4 inhibitors from several unique chemotypes (Figure ). ,− GSK2193874 was the first selective TRPV4 inhibitor to show prevention and resolution of lung edema in heart failure models . Subsequently, a series of piperidine benzimidazole TRPV4 inhibitors were discovered that replicated the in vivo pharmacology of GSK2193874 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of GSK3527497: A Candidate for the Inhibition of Transient Receptor Potential Vanilloid-4 (TRPV4)

et al. 2019

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GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.

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