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

Autor:	Brooks CA; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Barton LS; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Behm DJ; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Brnardic EJ; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Costell MH; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Holt DA; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Jolivette LJ; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Matthews JM; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., McAtee JJ; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., McCleland BW; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Patterson JR; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Pero JE; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Rivero RA; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Roethke TJ; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Sanchez RM; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Shenje R; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Terrell LR; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States., Lawhorn BG; Heart Failure Discovery Performance Unit and Flexible Discovery Unit , GlaxoSmithKline , Collegeville , Pennsylvania 19426 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Oct 24; Vol. 62 (20), pp. 9270-9280. Date of Electronic Publication: 2019 Oct 09.
DOI:	10.1021/acs.jmedchem.9b01247
Abstrakt:	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 CL u , Vdss u , and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdss u and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdss u in addition to bulk physicochemical properties. Optimization of CL u 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.
Databáze:	MEDLINE
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