α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: Exploration of conformational constraints in the acyl side chain

被引：5
作者：
Duncan, Katharine K.
Otrubova, Katerina
Boger, Dale L. [1 ]
机构：
[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 09期
基金：
美国国家卫生研究院;
关键词：
Fatty acid amide hydrolase; alpha-Ketoheterocycles; THERAPEUTIC TARGET; MOLECULAR CHARACTERIZATION; KETOOXAZOLE INHIBITORS; IRREVERSIBLE INHIBITOR; REVERSIBLE INHIBITORS; EXCEPTIONALLY POTENT; FAAH INHIBITOR; ANANDAMIDE; DISCOVERY; ENZYME;
D O I：
10.1016/j.bmc.2014.03.013
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
A series of alpha-ketooxazoles containing heteroatoms embedded within conformational constraints in the C2 acyl side chain of 2 (OL-135) were synthesized and evaluated as inhibitors of fatty acid amide hydrolase (FAAH). The studies reveal that the installation of a heteroatom (O) in the conformational constraint is achievable, although the potency of these novel derivatives is reduced slightly relative to 2 and the analogous 1,2,3,4-tetrahydronaphthalene series. Interestingly, both enantiomers (R and S) of the candidate inhibitors bearing a chiral center adjacent to the electrophilic carbonyl were found to effectively inhibit FAAH. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2763 / 2770
页数：8
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