2. Academic Validation
  3. Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)

Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)

  • ACS Med Chem Lett. 2019 Jul 15;10(8):1228-1233. doi: 10.1021/acsmedchemlett.9b00274.
Carl A Brooks 1,  Linda S Barton 1,  David J Behm 1,  Hilary S Eidam 1,  Ryan M Fox 1,  Marlys Hammond 1,  Tram H Hoang 1,  Dennis A Holt 1,  Mark A Hilfiker 1,  Brian G Lawhorn 1,  Jaclyn R Patterson 1,  Patrick Stoy 1,  Theresa J Roethke 1,  Guosen Ye 1,  Steve Zhao 1,  Kevin S Thorneloe 1,  Krista B Goodman 1,  Mui Cheung 1
Affiliations

Affiliation

  • 1 Heart Failure Discovery Performance Unit, GlaxoSmithKline, Metabolic Pathways and Cardiovascular Therapeutic Area, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
PMID: 31413810 DOI: 10.1021/acsmedchemlett.9b00274
Abstract

GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

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