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

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

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7016-7030
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number16
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Lee, K. S. S., Liu, J. Y., Wagner, K. M., Pakhomova, S., Dong, H., Morisseau, C., Fu, S. H., Yang, J., Wang, P., Ulu, A., Mate, C. A., Nguyen, L. V., Hwang, S. H., Edin, M. L., Mara, A. A., Wulff, H., Newcomer, M. E., Zeldin, D. C., & Hammock, B. D. (2014). Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. Journal of Medicinal Chemistry, 57(16), 7016-7030. https://doi.org/10.1021/jm500694p