Delineation of a fundamental alpha-ketoheterocycle substituent effect for use in the design of enzyme inhibitors.
The synthesis and examination of a systematic series of 5-substituted 2-keto oxazoles as inhibitors of fatty acid amide hydrolase (FAAH) defined a fundamental substituent effect that led to the discovery of inhibitors with Ki's as low as 400 pM. The intrinsic basis of the relationship (-log Ki vs sigmap), which relates Ki with the Hammett sigmap constant of the substituent, the magnitude of the effect (rho = 3.01), and its predictive value (R2 = 0.91) suggest a widespread applicability in studies beyond FAAH.
Romero
F Anthony
FA
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Hwang
Inkyu
I
Boger
Dale L
DL
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds