title: 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.
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , P.O. Box 9502, 2300 RA Leiden, Netherlands.
authors.forename: Freek J
authors.initials: FJ
authors.lastname: Janssen
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , P.O. Box 9502, 2300 RA Leiden, Netherlands.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Baggelaar
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , P.O. Box 9502, 2300 RA Leiden, Netherlands.
authors.forename: Jessica J A
authors.initials: JJ
authors.lastname: Hummel
authors.affiliation: Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University , P.O. Box 9502, 2300 RA Leiden, Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Chemistry, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , P.O. Box 9502, 2300 RA Leiden, Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D062126:Databases, Chemical; D057809:HEK293 Cells; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D007659:Ketones; D008071:Lipoprotein Lipase; D010080:Oxazoles; D011725:Pyridines; D000099252:Fatty Acid Amide Hydrolases