Exploration of a fundamental substituent effect of alpha-ketoheterocycle enzyme inhibitors: Potent and selective inhibitors of fatty acid amide hydrolase.
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)).
DeMartino
Jessica K
JK
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Garfunkle
Joie
J
Hochstatter
Dustin G
DG
Cravatt
Benjamin F
BF
Boger
Dale L
DL
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
D000581:Amidohydrolases; D010080:Oxazoles; D000099252:Fatty Acid Amide Hydrolases