title: Exploration of a fundamental substituent effect of alpha-ketoheterocycle enzyme inhibitors: Potent and selective inhibitors of fatty acid amide hydrolase.
abstract: A series of C4 substituted alpha-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 sigma(m) versus -logK(i) provided a linear correlation (R(2)=0.90) with a slope of 3.37 (rho=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 sigma(m) provides a >1000-fold change in K(i)).
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: DeMartino
authors.forename: Joie
authors.initials: J
authors.lastname: Garfunkle
authors.forename: Dustin G
authors.initials: DG
authors.lastname: Hochstatter
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D015195:Drug Design; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D010080:Oxazoles; D000099252:Fatty Acid Amide Hydrolases