184481-10-5Relevant articles and documents
Identification, Synthesis, and Characterization of a Major Circulating Human Metabolite of TRPV4 Antagonist GSK2798745
Pero, Joseph E.,McAtee, John J.,Behm, David J.,Briand, Jacques,Graczyk-Millbrandt, Grazyna,Erhard, Karl,Roberts, Andrew D.,Rivero, Ralph A.,Holt, Dennis A.,Lawhorn, Brian G.
supporting information, p. 1498 - 1502 (2021/09/13)
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.
Concise total syntheses of the sesquiterpenoids (-)-homalomenol A and (-)-homalomenol B
Piers, Edward,Oballa, Renata M.
, p. 8439 - 8447 (2007/10/03)
The conjugate additions of the organocopper(I) reagents 22 and 27 to the enantiomerically homogeneous bicyclic enone 4 provided, after epimerization (NaOMe, MeOH) of the resultant product mixtures and appropriate chromatographic separations, the bicyclo[4.3.0]nonan-2-ones 24 and 28. Compounds 24 and 28 were readily converted, via two synthetic steps in each case, into the sesquiterpenoids (-)-homalomenols B (2) and A (1), respectively.
