Janssen_2015_J.Med.Chem_58_9742

Diacylglycerol lipase alpha (DAGLalpha) is responsible for the formation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system. DAGLalpha inhibitors are required to study the physiological role of 2-AG. Previously, we identified the alpha-ketoheterocycles as potent and highly selective DAGLalpha inhibitors. Here, we present the first comprehensive structure-activity relationship study of alpha-ketoheterocycles as DAGLalpha inhibitors. Our findings indicate that the active site of DAGLalpha 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 DAGLalpha homology model. Altogether, our results may guide the design of future DAGLalpha inhibitors as leads for molecular therapies to treat neuroinflammation, obesity, and related metabolic disorders.