C O M M U N I C A T I O N S
(-log Ki) and the magnitude of the effect (F ) 3.01) provides a
useful new predictive tool for the rational design of serine and
cysteine protease and hydrolase inhibitors.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (DA15648) and the
Skaggs Institute for Chemical Biology, and the postdoctoral
fellowship support for F.A.R. (American Cancer Society).
Supporting Information Available: Full experimental details and
characterization, and FAAH assay measurement errors of the inhibitors
disclosed herein. This material is available free of charge via the Internet
Figure 2. FAAH inhibition. Ki measurement errors are provided in
Supporting Information.
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Figure 3. Value of -log Ki (µM) versus σp.
character of the C2 carbonyl imparted by the electron-withdrawing
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-
as the carboxylate anion (-CO2 vs -CO2H, σp ) 0.11 vs 0.44)
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1
C5, but not C2; H and 13C NMR) and inhibit the enzyme with
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σp and Ki is sufficiently dependable that deviations from expecta-
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two of the more potent inhibitors in Figure 2 (5f and 5g) were
retrospectively prepared and examined based on this relationship.
Notably, 5c, 5i, and 5k bearing the strongest electron-withdrawing
substituents display subnanomolar FAAH inhibitory potency. While
additional substituent features can and will further modulate the
binding affinity of the candidate inhibitors (e.g., H-bonding,
hydrophobic or steric interactions),33 the magnitude of the electronic
effect of the substituent (F ) 3.01) on the activity of a conjugated
R-ketoheterocycle (Ki) suggests the latter will dominate, especially
with small and simple substituents.
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(31) A reviewer has suggested that this may also arise from an increased H-bond
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(32) An anomalous σp of 0.22 is occasionally reported for -CHO (vs 0.42)
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(33) An example is provided in Supporting Information.
The delineation of a fundamental correlation that relates the
Hammett σp constant of a substituent with its enzyme inhibition
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