Reema K. Thalji; Jeff J. McAtee; Svetlana L. Belyanskaya; Martin Brandt; Gregory D. Brown; Melissa H. Costell; Yun Ding; Jason W. Dodson; Steve H. Eisennagel; Rusty E. Fries; Jeffrey W. Gross; Mark R. Harpel; Dennis A. Holt; David I. Israel; Larry J. Jolivette; Daniel Krosky; Hu Li; Quinn Lu; Tracy Mandichak; Theresa Roethke; Christine G. Schnackenberg; Benjamin Schwartz; Lisa M. Shewchuk; Wensheng Xie; David J. Behm; Stephen A. Douglas; Ami L. Shaw; Joseph P. Marino Jr.
Bioorg. Med. Chem. Lett., 2013, 23, 3584-3588
https://doi.org/10.1016/j.bmcl.2013.04.019

Abstract

1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.