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Discovery of GSK3527497: A Candidate for the Inhibition of Transient Receptor Potential Vanilloid-4 (TRPV4). | LitMetric
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors and . Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CL, Vdss, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdss and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdss in addition to bulk physicochemical properties. Optimization of CL 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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