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

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.

[1]  D. Behm,et al.  TRPV4 antagonists: a patent review (2015-2020). , 2021, Expert opinion on therapeutic patents.

[2]  Bruce D. Johnson,et al.  Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: a randomized, controlled pilot trial , 2020, European journal of heart failure.

[3]  D. Behm,et al.  Recent advances in TRPV4 agonists and antagonists. , 2020, Bioorganic & medicinal chemistry letters.

[4]  Carl A. Brooks,et al.  Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4). , 2019, ACS medicinal chemistry letters.

[5]  D. Sprecher,et al.  Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class TRPV4 Ion Channel Inhibitor, GSK2798745, in Healthy and Heart Failure Subjects , 2019, American Journal of Cardiovascular Drugs.

[6]  Carl A. Brooks,et al.  Design and Optimization of Sulfone Pyrrolidine Sulfonamide Antagonists of Transient Receptor Potential Vanilloid-4 with in Vivo Activity in a Pulmonary Edema Model. , 2018, Journal of medicinal chemistry.

[7]  Carl A. Brooks,et al.  Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4). , 2018, Journal of medicinal chemistry.

[8]  S. Matalon,et al.  TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. , 2014, American journal of physiology. Lung cellular and molecular physiology.

[9]  R Scott Obach,et al.  Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy , 2013, Pharmacological Reviews.

[10]  H. Alsaid,et al.  An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure , 2012, Science Translational Medicine.

[11]  M. Pellegatti Preclinical in vivo ADME studies in drug development: a critical review , 2012, Expert opinion on drug metabolism & toxicology.

[12]  V. Rawal,et al.  Total synthesis of N-methylwelwitindolinone D isonitrile. , 2011, Journal of the American Chemical Society.

[13]  K. Nicolaou,et al.  Total synthesis of kinamycins C, F, and J. , 2007, Journal of the American Chemical Society.

[14]  S. Hanessian,et al.  Catalytic asymmetric conjugate addition of nitroalkanes to cycloalkenones. , 2000, Organic letters.