Exploration of a fundamental substituent effect of α-ketoheterocycle enzyme inhibitors: Potent and selective inhibitors of fatty acid amide hydrolase

Abstract: A series of C4 substituted α-ketooxazoles were examined as inhibitors of the serine hydrolase fatty acid amide hydrolase in efforts that further define and generalize a fundamental substituent effect on enzyme inhibitory potency. Thus, a plot of the Hammett σ m versus −log K i provided a linear correlation (R 2 =0.90) with a slope of 3.37 (ρ =3.37), that is of a magnitude that indicates that of the electron-withdrawing character of the substituent dominates its effects (a one unit change in σ m provides a >1000-fold change in K i). [Copyright &y& Elsevier]