Comprehensive Analysis of Structure–Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors
详细信息 查看全文
- 作者：Freek J. Janssen ; Marc P. Baggelaar ; Jessica J. A. Hummel ; Herman S. Overkleeft ; Benjamin F. Cravatt ; Dale L. Boger ; Mario van der Stelt
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：December 24, 2015
- 年：2015
- 卷：58
- 期：24
- 页码：9742-9753
- 全文大小：493K
- ISSN：1520-4804
文摘
Diacylglycerol lipase α (DAGLα) is responsible for the formation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system. DAGLα inhibitors are required to study the physiological role of 2-AG. Previously, we identified the α-ketoheterocycles as potent and highly selective DAGLα inhibitors. Here, we present the first comprehensive structure–activity relationship study of α-ketoheterocycles as DAGLα inhibitors. Our findings indicate that the active site of DAGLα is remarkably sensitive to the type of heterocyclic scaffold with oxazolo-4N-pyridines as the most active framework. We uncovered a fundamental substituent effect in which electron-withdrawing meta-oxazole substituents increased inhibitor potency. (C6–C9)-acyl chains with a distal phenyl group proved to be the most potent inhibitors. The integrated SAR data was consistent with the proposed binding pose in a DAGLα homology model. Altogether, our results may guide the design of future DAGLα inhibitors as leads for molecular therapies to treat neuroinflammation, obesity, and related metabolic disorders.