| Literature DB >> 23664879 |
Reema K Thalji1, Jeff J McAtee, Svetlana 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.
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. Published by Elsevier Ltd.Entities:
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Year: 2013 PMID： 23664879 DOI： 10.1016/j.bmcl.2013.04.019
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823