Potent and Selective -Ketoheterocycle-Based Inhibitors of the Anandamide and Oleamide Catabolizing Enzyme, Fatty Acid Amide Hydrolas

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• 作者：F. Anthony Romero ; Wu Du ; Inkyu Hwang ; Thomas J. Rayl ; F. Scott Kimball ; Donmienne Leung ; Heather S. Hoover ; Richard L. Apodaca ; J. Guy Breitenbucher ; Benjamin F. Cravatt ; Dale L. Boger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：March 8, 2007
• 年：2007
• 卷：50
• 期：5
• 页码：1058 - 1068
• 全文大小：255K
• 年卷期：v.50,no.5(March 8, 2007)
• ISSN：1520-4804

文摘

A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amidehydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substitutedbenzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position withselected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect ofsubstitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituentswas also explored and revealed that the K_i follows a well-defined correlation with the Hammett _p constant( = 3.01, R² = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitorswith K_is as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitelyselective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5substituent = H) for the enzyme TGH.