935265-04-6Relevant articles and documents
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.
