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J Med Chem. 2018 Apr 26;61(8):3541-3550. doi: 10.1021/acs.jmedchem.7b01804. Epub 2018 Apr 10.

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

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Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center , University of California Davis , One Shields Avenue , Davis , California 95616 , United States.
Department of Pharmacology , University of California Davis , One Shields Avenue , Davis , California 95616 , United States.
VA Northern California Health Care System , Mather , California 95655 , United States.
Institute of Pharmaceutical Chemistry , Goethe-University Frankfurt , Max-von-Laue-Strasse 9 , D-60438 Frankfurt am Main , Germany.


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.

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