PF-3845

PF-3845 is a potent, selective, and irreversible fatty acid amide hydrolase (FAAH) inhibitor with a Ki of 0.23 μM. Fatty acid amide hydrolase (FAAH) is an enzyme that catalyzes N-acyl ethanolamines (NAEs), including the endocannabinoid arachidonoyl ethanolamide (AEA). Mechanistic and structural studies demonstrated that PF-3845 acts as a covalent inhibitor and carbamylates the active site serine241 of FAAH. PF-3845 covalently binds FAAH on Ser241 at the catalytic site, resulting in prolonged elevation of AEA in the brain and plasma in rats after treatment. Initial experiments indicated that PF-3845 is 10 to 20 times more potent than other FAAH inhibitors and has superior pharmacokinetic properties. PF-3845 significantly and persistently blockes inflammatory pain in rats through a cannabinoid receptor-dependent mechanism. In animal studies, PF-3845 elevated brain anandamide levels for up to 24 hours and produced a marked cannabinoid receptor-dependent reduction in inflammatory pain.