Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.

Authors: Lee, Kin Sing Stephen; Liu, Jun-Yan; Wagner, Karen M; Pakhomova, Svetlana; Dong, Hua; Morisseau, Christophe; Fu, Samuel H; Yang, Jun; Wang, Peng; Ulu, Arzu; Mate, Christina A; Nguyen, Long V; Hwang, Sung Hee; Edin, Matthew L; Mara, Alexandria A; Wulff, Heike; Newcomer, Marcia E; Zeldin, Darryl C; Hammock, Bruce D

Published In J Med Chem, (2014 Aug 28)

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.

PubMed ID: 25079952 Exiting the NIEHS site

MeSH Terms: Administration, Oral; Amines/pharmacology; Analgesics/pharmacology; Animals; Biological Availability; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Cyclohexanecarboxylic Acids/pharmacology; Diabetes Mellitus, Type 1/complications; Diabetic Neuropathies/drug therapy*; Diabetic Neuropathies/metabolism; Drug Design; Enzyme Inhibitors/chemistry*; Enzyme Inhibitors/pharmacokinetics; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Gabapentin; Humans; Male; Mice; Molecular Targeted Therapy; Neuralgia/drug therapy; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship; Time Factors; gamma-Aminobutyric Acid/pharmacology

Back
to Top