Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain

René Blöcher, Karen M. Wagner, Raghavender R. Gopireddy, Todd R. Harris, Hao Wu, Bogdan Barnych, Sung Hee Hwang, Yang Kevin Xiang, Ewgenij Proschak, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood (Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h. Additionally, MPPA does not alter self-motivated exploration of rats with inflammatory pain or the withdrawal latency in control rats.

Original languageEnglish (US)
Pages (from-to)3541-3550
Number of pages10
JournalJournal of Medicinal Chemistry
Volume61
Issue number8
DOIs
StatePublished - Apr 26 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Blöcher, R., Wagner, K. M., Gopireddy, R. R., Harris, T. R., Wu, H., Barnych, B., Hwang, S. H., Xiang, Y. K., Proschak, E., Morisseau, C., & Hammock, B. D. (2018). Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain. Journal of Medicinal Chemistry, 61(8), 3541-3550. https://doi.org/10.1021/acs.jmedchem.7b01804