1-Heteroarylpropan-2-ones as inhibitors of fatty acid amide hydrolase: Studies on structure-activity relationships and metabolic stability

被引：9
|
作者：
Zahov, Stefan [1 ]
Garzinsky, David [1 ]
Hanekamp, Walburga [1 ]
Lehr, Matthias [1 ]
机构：
[1] Univ Munster, Inst Pharmaceut & Med Chem, Corrensstr 48, D-48149 Munster, Germany
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 03期
关键词：
Propan-2-one; Fatty acid amide hydrolase; Enzyme inhibition; Metabolic stability; Aqueous solubility; CYTOSOLIC PHOSPHOLIPASE A(2)ALPHA; CANNABINOID RECEPTORS; DUAL INHIBITORS; SYSTEM; FAAH; ENDOCANNABINOIDS; PAIN; 1-HETEROARYL-3-PHENOXYPROPAN-2-ONES; 1-INDOL-1-YL-PROPAN-2-ONES; CLASSIFICATION;
D O I：
10.1016/j.bmc.2016.11.025
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：
The serine hydrolase fatty acid amide hydrolase (FAAH) catalyzes the degradation of the endocannabinoid anandamide, which possesses analgesic and anti-inflammatory effects. A new series of 1-heteroarylpropan-2-ones was synthesized and evaluated for FAAH inhibition. Structure-activity relationship studies revealed that 1H-benzotriazol-1-yl, 1H-7-azabenzotriazol-1-yl, 1H-tetrazol-1-y1 and 2H-tetrazol-2-yl substituents have the highest impact on inhibitory potency. Furthermore, attempts were made to increase the limited metabolic stability of the ketone functionality of these compounds towards metabolic reduction by introduction of shielding alkyl substituents in proximity of this serine reactive group. (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码：825 / 837
页数：13
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