Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model

Abstract Conceptual design and modification of urea moiety in chemotypePF-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).