Abstract
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.
| Original language | English (US) |
|---|---|
| Journal | Prostaglandins and Other Lipid Mediators |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- Isosteres
- Liver microsomal stability assay
- Non-urea sEH inhibitors
- Soluble epoxide hydrolase (sEH)
- Structure activity relationship (SAR) study
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Pharmacology
- Cell Biology
Cite this
Novel piperidine-derived amide sEH inhibitors as mediators of lipid metabolism with improved stability. / Pecic, Stevan; Zeki, Amir; Xu, Xiaoming; Jin, Gina Y.; Zhang, Shuwei; Kodani, Sean; Halim, Marlin; Morisseau, Christophe; Hammock, Bruce D.; Deng, Shi Xian.
In: Prostaglandins and Other Lipid Mediators, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel piperidine-derived amide sEH inhibitors as mediators of lipid metabolism with improved stability
AU - Pecic, Stevan
AU - Zeki, Amir
AU - Xu, Xiaoming
AU - Jin, Gina Y.
AU - Zhang, Shuwei
AU - Kodani, Sean
AU - Halim, Marlin
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Deng, Shi Xian
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Isosteres
KW - Liver microsomal stability assay
KW - Non-urea sEH inhibitors
KW - Soluble epoxide hydrolase (sEH)
KW - Structure activity relationship (SAR) study
UR - http://www.scopus.com/inward/record.url?scp=85044255392&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044255392&partnerID=8YFLogxK
U2 - 10.1016/j.prostaglandins.2018.02.004
DO - 10.1016/j.prostaglandins.2018.02.004
M3 - Article
C2 - 29567338
AN - SCOPUS:85044255392
JO - Prostaglandins and Other Lipid Mediators
JF - Prostaglandins and Other Lipid Mediators
SN - 1098-8823
ER -