Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (−)-12a, (−)-12i, (−)-12l–m. The required (−)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (−)-12l and (−)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3–30 mg/kg po for 7 days. The effects at 30 mg/kg are comparable to that of PF-04457845 (10 mg/kg) and Tramadol (40 mg/kg).

化学型PF-3845 / 04457845（一种基准标记的脂肪酸酰胺水解酶（FAAH）的不可逆抑制剂）中尿素部分的概念设计和修饰导致发现了一种新型的具有可逆作用机理的基于烟酰胺的铅12a。在12a中将SAR集中在吡啶杂环（Ar）周围（表1和2）（表1和表2），形成了四个候选化合物（-）- 12a，（-）- 12i，（-）- 12l – m。通过新型手性不对称中间体15的非对映异构体拆分获得所需的（-）-对映体。基于FAAH效力，在肝微粒体代谢稳定性的比较曲线，抑制主要hCYP450同种型，大鼠PK，和脑渗透能力的责任，二SAR优化化合物，（ - ） - 12升和（ - ） - 12米，被选择用于功效化疗诱发的周围神经病变（CIPN）大鼠模型的研究。当以3–30 mg / kg口服7天后，这两种化合物均显示出与剂量相关的抗痛觉过敏作用。30 mg / kg的作用与PF-04457845（10 mg / kg）和曲马多（40 mg / kg）的作用相当。