- Potent and selective α-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase
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A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the Ki follows a well-defined correlation with the Hammett σp constant (ρ = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with Kis as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.
- Romero, F. Anthony,Du, Wu,Hwang, Inkyu,Rayl, Thomas J.,Kimball, F. Scott,Leung, Donmienne,Hoover, Heather S.,Apodaca, Richard L.,Breitenbucher, J. Guy,Cravatt, Benjamin F.,Boger, Dale L.
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p. 1058 - 1068
(2008/02/02)
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- Delineation of a fundamental α-ketoheterocycle substituent effect for use in the design of enzyme inhibitors
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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 σp), which relates Ki with the Hammett σp constant of the substituent, the magnitude of the effect (ρ = 3.01), and its predictive value (R2 = 0.91) suggest a widespread applicability in studies beyond FAAH. Copyright
- Romero, F. Anthony,Hwang, Inkyu,Boger, Dale L.
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p. 14004 - 14005
(2007/10/03)
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- Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics
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Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
- Boger, Dale L.,Miyauchi, Hiroshi,Du, Wu,Hardouin, Christophe,Fecik, Robert A.,Cheng, Heng,Hwang, Inkyu,Hedrick, Michael P.,Leung, Donmienne,Acevedo, Orlando,Guimar?es, Cristiano R. W.,Jorgensen, William L.,Cravatt, Benjamin F.
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p. 1849 - 1856
(2007/10/03)
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