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3044598 
Journal Article 
Comprehensive Analysis of Structure Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors 
Janssen, FJ; Baggelaar, MP; Hummel, JJ; Overkleeft, HS; Cravatt, BF; Boger, DL; van der Stelt, M 
2015 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
English 
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.