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.
J Med Chem. 2018 Apr 26;61(8):3541-3550. doi: 10.1021/acs.jmedchem.7b01804. Epub 2018 Apr 10.
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 ( T = 30 min; C = 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.
受先前发现的可溶性环氧化物水解酶 (sEH) 和磷酸二酯酶 4 (PDE4) 抑制剂之间增强的镇痛疗效的启发，我们设计、合成并表征了 21 种新型 sEH/PDE4 双重抑制剂。其中最好的一种在体外试验中显示出良好的疗效。进一步对 4 种选定化合物的一部分进行药代动力学研究，确定了一种可生物利用的双重抑制剂 N-(4-甲氧基-2-(三氟甲基)苄基)-1-丙酰基哌啶-4-甲酰胺 (MPPA)。在脂多糖诱导的炎性疼痛大鼠模型中，MPPA 在口服 3 mg/kg 后迅速在血液中增加（T = 30 分钟；C = 460 nM），并在 4 小时的时间过程中与血液水平相关，具有快速作用开始的抗炎性疼痛。此外，MPPA 不会改变炎性疼痛大鼠的自发探索或对照大鼠的退缩潜伏期。
