| Abstract
| - Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fattyacid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypesin rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists,indicating that FAAH may represent an attractive therapeutic target for treatment of pain, inflammation,and other central nervous system disorders. However, the FAAH inhibitors reported to date lack drug-like pharmacokinetic properties and/or selectivity. Herein we describe piperidine/piperazine ureasrepresented by N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750) and N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (PF-622) as a novel mechanistic class of FAAH inhibitors.PF-750 and PF-622 show higher in vitro potencies than previously established classes of FAAH inhibitors.Rather unexpectedly based on the high chemical stability of the urea functional group, PF-750 and PF-622 were found to inhibit FAAH in a time-dependent manner by covalently modifying the enzyme'sactive site serine nucleophile. Activity-based proteomic profiling revealed that PF-750 and PF-622 werecompletely selective for FAAH relative to other mammalian serine hydrolases. We hypothesize that thisremarkable specificity derives, at least in part, from FAAH's special ability to function as a C(O)−Nbond hydrolase, which distinguishes it from the vast majority of metabolic serine hydrolases in mammalsthat are restricted to hydrolyzing esters and/or thioesters. The piperidine/piperazine urea may thus representa privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedentedcombination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.
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