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

• Published in: Bioorganic & medicinal chemistry 2008-11, Vol.18 (22), p.5842-5846
• Main Authors: DeMartino, Jessica K., Garfunkle, Joie, Hochstatter, Dustin G., Cravatt, Benjamin F., Boger, Dale L.
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Drug Design; Enzymes and enzyme inhibitors; Fatty acid amide hydrolase; Fundamental and applied biological sciences. Psychology; Hydrolases; Medical sciences; Miscellaneous; Molecular Structure; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacokinetics; Oxazoles - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.06.084

A series of C4 substituted α-ketooxazoles were examined as inhibitors of fatty acid amide hydrolase in efforts that further define and generalize a fundamental substituent effect on enzyme inhibitory potency. 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).