Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745.

Abstract

GSK2798745, an antagonist of the transient receptor potential vanilloid 4 (TRPV4) ion channel, was recently investigated in clinical trials for the treatment of cardiac and respiratory diseases. Human plasma and urine samples collected from healthy volunteers following oral administration were analyzed to identify circulating and excreted metabolites of the parent drug. One major circulating metabolite (1) was found in pooled human plasma samples, accounting for approximately half of the observed drug-related material. Isolation of metabolite 1 from urine samples followed by MS and NMR studies led to a putative structural assignment of 1 where hydroxylation of GSK2798745 occurred on the central ring, producing a penta-substituted cyclohexane structure containing three stereocenters. Two unique chemical syntheses of the proposed structure were developed to confirm the identity of metabolite 1 and provide access to gram quantities for biological characterization.

• Authors: Joseph E Pero, John J McAtee, David J Behm, Jacques Briand, Grazyna Graczyk-Millbrandt, Karl Erhard, Andrew D Roberts, Ralph A Rivero, Dennis A Holt, Brian G Lawhorn
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 12 Issue 9 Pg. 1498-1502 (Sep 09 2021) ISSN: 1948-5875 [Print] United States
• PMID: 34531959 (Publication Type: Journal Article)
• Copyright: © 2021 American Chemical Society.