| abstract |
Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having K 1 's below 200 pM and activities 10 2 -10 3 times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an α-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other π-unsaturation corresponding to the arachidonyl Δ 8,9 /Δ 11,12 and/or oleyl Δ 9,10 positions. A preferred α-keto heterocylic head group is α-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). |