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 Vol. 18; no. 22; pp. 5842 - 5846
• Main Authors: DeMartino, Jessica K., Garfunkle, Joie, Hochstatter, Dustin G., Cravatt, Benjamin F., Boger, Dale L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2008; Elsevier
• 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; Fatty acid amide hydrolase; Five membered ring; Nitrile; Enzyme; Aliphatic compound; Nitrogen heterocycle; Amidase; Enzyme inhibitor; Selectivity; In vitro; Pyridine derivatives; Position isomer; Structure activity relation; Carboxylic acid; Hydrolases; Fluorine Organic compounds; Chemical synthesis; Oxazole derivatives; Oxygen nitrogen heterocycle
• 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).