Novel piperidine-derived amide sEH inhibitors as mediators of lipid metabolism with improved stability

Publication date: Available online 20 March 2018 Source:Prostaglandins & Other Lipid Mediators Author(s): Stevan Pecic, Amir A. Zeki, Xiaoming Xu, Gina Y. Jin, Shuwei Zhang, Sean Kodani, Marlin Halim, Christophe Morisseau, Bruce D. Hammock, Shi-Xian Deng We have previously identified and reported several potent piperidine-derived amide inhibitors of the human soluble epoxide hydrolase (sEH) enzyme. The inhibition of this enzyme leads to elevated levels of epoxyeicosatrienoic acids (EETs), which are known to possess anti-inflammatory, vasodilatory, and anti-fibrotic effects. Herein, we report the synthesis of 9 analogs of the lead sEH inhibitor and the follow-up structure-activity relationship and liver microsome stability studies. Our findings show that isosteric modifications that lead to significant alterations in the steric and electronic properties at a specific position in the molecule can reduce the efficacy by up to 75-fold. On the other hand, substituting hydrogen with deuterium produces a notable increase (∼30%) in the molecules’ half-lives in both rat and human microsomes, while maintaining sEH inhibition potency. These data highlight the utility of isosteric replacement for improving bioavailability, and the newly-synthesized inhibitor structures may thus, serve as a starting point for preclinical development. Our docking study reveals that in the catalytic pocket of sEH, these analogs are in proximity of the key amino acids involved in hydr...
Source: Prostaglandins and Other Lipid Mediators - Category: Lipidology Source Type: research