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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Blocher R, Wagner KM, Gopireddy RR, Harris TR, Wu H, Barnych B, Hwang SH, Xiang YK, Proschak E, Morisseau C, Hammock BD (2018) Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain Journal of Medicinal Chemistry61: 3541-3550
Blocher R, Wagner KM, Gopireddy RR, Harris TR, Wu H, Barnych B, Hwang SH, Xiang YK, Proschak E, Morisseau C, Hammock BD (2018) Journal of Medicinal Chemistry61: 3541-3550