posted on 2021-08-30, 19:47authored byJoseph 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
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.