Amelioration of PXR-mediated CYP3A4 induction by mGluR2 modulators

Bioorganic & Medicinal Chemistry Letters
Roy J VazRaymond Kosley

Abstract

This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5) induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric mechanism. The compounds were initially shown to induce CYP3A4/5 via the gold-standard induction assay measured in primary human hepatocytes. This was followed up by testing the compounds in a PXR assay which correlated well with the assay in primary cells. Further, one of the compounds was crystallized with PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with previously published PXR co-crystal structures, lead to modification ideas. The compounds synthesized based on these ideas were shown not to be CYP3A4/5 inducers. The mGluR2 activity of the resulting compounds was maintained.

Citations

Nov 25, 2020·Environmental Science & Technology·Thanh T LaiAngela K Wilson
Mar 7, 2020·Journal of Chemical Information and Modeling·Michael J BowerBrian Goldman
Sep 18, 2021·ACS Medicinal Chemistry Letters·Joshi M RamanjuluRobert W Marquis
Oct 27, 2021·Critical Reviews in Food Science and Nutrition·Jie ZhangTiehua Zhang

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