Structure-Activity Relationships of -Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase

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• 作者：Christophe Hardouin ; Michael J. Kelso ; F. Anthony Romero ; Thomas J. Rayl ; Donmienne Leung ; Inkyu Hwang ; Benjamin F. Cravatt ; Dale L. Boger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：July 12, 2007
• 年：2007
• 卷：50
• 期：14
• 页码：3359 - 3368
• 全文大小：249K
• 年卷期：v.50,no.14(July 12, 2007)
• ISSN：1520-4804

文摘

A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acidamide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements orsubstituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K_i =2.6 nM), with 5hh (aryl = 3-ClPh, K_i = 900 pM) being 5-fold more potent than 2b. Conformationallyrestricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j(ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O,NMe, S), electron-withdrawing groups (SO, SO₂), and amides positioned within and hydroxyl substitutionson the linking side chain were investigated, which typically led to a loss in potency. The most tolerantpositions provided effective inhibitors (12p, 6-position S, K_i = 3 nM, or 13d, 2-position OH, K_i = 8 nM)comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of>100 candidates prepared revealed that they are selective for FAAH over all other mammalian serineproteases.