Concise Syntheses of Microsomal Metabolites of a Potent OXE (Oxoeicosanoid) Receptor Antagonist

Shishir Chourey; Rui Wang; Qiuji Ye; Chintam Nagendra Reddy; Shiyu Sun; Norito Takenaka; William S. Powell; Joshua Rokach

doi:10.1248/cpb.c22-00926

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Concise Syntheses of Microsomal Metabolites of a Potent OXE (Oxoeicosanoid) Receptor Antagonist

Shishir Chourey , Rui Wang, Qiuji Ye, Chintam Nagendra Reddy, Shiyu Sun, Norito Takenaka, William S. Powell, Joshua Rokach

Author information

Shishir Chourey Corresponding author
Claude Pepper Institute and Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology
Rui Wang
Claude Pepper Institute and Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology
Qiuji Ye
Claude Pepper Institute and Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology
Chintam Nagendra Reddy
Claude Pepper Institute and Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology
Shiyu Sun
Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology
Norito Takenaka
Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology
William S. Powell
Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre
Joshua Rokach Corresponding author
Claude Pepper Institute and Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology

Keywords: 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid, oxoeicosanoid (OXE) receptor antagonist, microsome, metabolite, hemiaminal, porcine liver esterase

JOURNAL FREE ACCESS FULL-TEXT HTML

2023 Volume 71 Issue 7 Pages 534-544

DOI https://doi.org/10.1248/cpb.c22-00926

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Abstract

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is the most potent eosinophil chemoattractant among lipid mediators, and its actions are mediated by the selective oxoeicosanoid (OXE) receptor. Our group previously developed a highly potent indole-based OXE antagonist, S-C025, with an IC₅₀ value of 120 pM. S-C025 was converted to a number of metabolites in the presence of monkey liver microsomes. Complete chemical syntheses of authentic standards enabled us to identify that the four major metabolites were derived by the oxidation at its benzylic and N-methyl carbon atoms. Herein we report concise syntheses of the four major metabolites of S-C025.

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