| Abstract
| - A study of the structure−activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amidehydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substitutedbenzene derivatives (12−14) revealed that the optimal position for substitution was the meta-position withselected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect ofsubstitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituentswas also explored and revealed that the Ki follows a well-defined correlation with the Hammett σp constant(ρ = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitorswith Kis as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitelyselective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5substituent = H) for the enzyme TGH.
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