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

Autor: Shuwei Zhang, Gina Y. Jin, Amir A. Zeki, Christophe Morisseau, Stevan Pecic, Bruce D. Hammock, Shi Xian Deng, Marlin Halim, Sean D. Kodani, Xiaoming Xu
Rok vydání: 2017
Předmět:
0301 basic medicine
Epoxide hydrolase 2
Male
Biochemistry & Molecular Biology
Physiology
Stereochemistry
Medical Biochemistry and Metabolomics
01 natural sciences
Biochemistry
Article
03 medical and health sciences
chemistry.chemical_compound
Liver microsomal stability assay
Piperidines
Amide
Animals
Humans
Enzyme Inhibitors
Pharmacology
chemistry.chemical_classification
Epoxide Hydrolases
Lipid metabolism
Cell Biology
Lipid Metabolism
Amides
0104 chemical sciences
Amino acid
Non-urea sEH inhibitors
Rats
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
030104 developmental biology
Enzyme
Soluble epoxide hydrolase
chemistry
Docking (molecular)
5.1 Pharmaceuticals
Microsome
cardiovascular system
Isosteres
Female
Development of treatments and therapeutic interventions
Structure activity relationship (SAR) study
Zdroj: Prostaglandinsother lipid mediators. 136
ISSN: 1098-8823
Popis: 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 hydrolysis of EETs.
Databáze: OpenAIRE
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