Comprehensive Analysis of Structure-Activity Relationships of ?-Ketoheterocycles as sn-1-Diacylglycerol Lipase ? Inhibitors.

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

SUBMITTER: Janssen FJ 

PROVIDER: S-EPMC4690813 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature