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Delineation of a fundamental alpha-ketoheterocycle substituent effect for use in the design of enzyme inhibitors.

ABSTRACT: 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.

SUBMITTER: Romero FA 

PROVIDER: S-EPMC2501112 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Delineation of a fundamental alpha-ketoheterocycle substituent effect for use in the design of enzyme inhibitors.

Romero F Anthony FA   Hwang Inkyu I   Boger Dale L DL  

Journal of the American Chemical Society 20061101 43

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 studie  ...[more]

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