期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 50, 期 5, 页码 1058-1068出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm0611509
关键词
-
资金
- NIDA NIH HHS [DA15648, R01 DA015648, R01 DA015197, P01 DA017259, R01 DA015648-05, DA015197, DA017259] Funding Source: Medline
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, R-2 = 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据