Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Aug 1

PMID 25079952

Citations 47

Authors

Kin Sing Stephen Lee

Jun-Yan Liu

Karen M Wagner

Svetlana Pakhomova

Hua Dong

Christophe Morisseau

Samuel H Fu

Jun Yang

Peng Wang

Arzu Ulu

Christina A Mate

Long V Nguyen

Sung Hee Hwang

Matthew L Edin

Alexandria A Mara

Heike Wulff

Marcia E Newcomer

Darryl C Zeldin

Bruce D Hammock

Affiliations

Soon will be listed here.

Abstract

Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.

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