808134-95-4Relevant academic research and scientific papers
Potent and selective α-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase
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.
, p. 1058 - 1068 (2008/02/02)
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.
Delineation of a fundamental α-ketoheterocycle substituent effect for use in the design of enzyme inhibitors
Romero, F. Anthony,Hwang, Inkyu,Boger, Dale L.
, p. 14004 - 14005 (2007/10/03)
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
Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics
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.
, p. 1849 - 1856 (2007/10/03)
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.
