Inhibitors of fatty acid amide hydrolase

摘要

Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having K₁'s below 200 pM and activities 10²-10³ times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an alpha-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other pi-unsaturation corresponding to the arachidonyl Delta^8,9/Delta^11,12 and/or oleyl Delta^9,10 positions. A preferred alpha-keto heterocylic head group is alpha-keto N4 oxazolopyridine, with incorporation of a second weakly basic nitrogen. Fatty acid amide hydrolase is an enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid receptors).