Comprehensive Analysis of Structure–Activity Relationships of α-Ketoheterocycles as sn-1-Diacylglycerol Lipase α Inhibitors

Abstract

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.

Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors

“…His650 is part of the catalytic triad and has been postulated to bind in this manner before, based on the covalent docking of α-ketoheterocycles in a homology model of DAGL-α. 41 Additionally, compound 1 forms a strong π-stacking interaction with His471 and a stable hydrogen bonding interaction with Tyr303, explaining the difference in potency observed with 2 , which forms a π-stacking interaction with His650, and less stable hydrogen bonding interaction with the nitrogen in position 1 and His471 (Figure S3). Compound 4 is also able to make this very stable hydrogen bonding between the nitrogen in position 2 and His650, potentially explaining the intermediate potency.…”

Endocannabinoid Turnover

“…On the other hand, whereas pharmacological approaches have the advantage of temporal resolution, they can be limited by drug availability and selectivity; for review, see Janssen and van der Stelt (2016). In the case of the DAGLs, the historical pharmacological studies have largely relied on the use of RHC80267 and/or tetrahydrolipstatin (THL), but results obtained with them have sometimes been contentious as although they can inhibit DAGL activity they also inhibit other serine lipases and can show poor tissue penetration (Hoover et al, 2008;Janssen et al, 2015). A set of centrally active DAGL inhibitors has recently been developed that, when used with appropriate controls, has allowed for the analysis of the effects of acute inhibition of DAGL activity on lipid networks in the brain (Ogasawara et al, 2016).…”

Chiral disubstituted piperidinyl ureas: a class of dual diacylglycerol lipase-α and ABHD6 inhibitors

“…Previously, we have reported the discovery of α-ketoheterocycles, 11 – 13 glycinesulfonamides 14 and triazole ureas ( e.g. DO34 and DH376 ( 1 )), 15 as selective DAGL inhibitors ( Fig.…”