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Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.

Abstract：

: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 K(i) follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Romero FA,Du W,Hwang I,Rayl TJ,Kimball FS,Leung D,Hoover HS,Apodaca RL,Breitenbucher JG,Cravatt BF,Boger DL

doi

10.1021/jm0611509

subject

Has Abstract

pub_date

2007-03-08 00:00:00

pages

1058-68

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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