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

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.受此前报道的可溶性环氧化物水解酶（soluble epoxide hydrolase, sEH）与磷酸二酯酶4（phosphodiesterase 4, PDE4）抑制剂联用可增强镇痛活性的研究成果启发，本研究设计、合成并表征了21种新型sEH/PDE4双重抑制剂。其中活性最优的化合物在体外实验中展现出良好的药效。对筛选出的4种化合物开展进一步药代动力学研究后，我们成功鉴定出一种具有生物利用度的双重抑制剂N-(4-甲氧基-2-(三氟甲基)苄基)-1-丙酰基哌啶-4-甲酰胺（MPPA）。在脂多糖（lipopolysaccharide, LPS）诱导的炎性疼痛大鼠模型中，以3 mg/kg剂量口服给予MPPA后，其血药浓度迅速达峰（达峰时间Tmax=30 min，峰浓度Cmax=460 nM），并在4小时的观测周期内以快速起效的方式缓解炎性疼痛，其镇痛效果与血药浓度水平密切相关。此外，MPPA不会改变炎性疼痛大鼠的自主探索行为，也不会对正常对照组大鼠的缩爪潜伏期产生影响。