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Comprehensive analysis of structure-activity relationships of a-ketoheterocycles as sn-1-diacylglycerol lipase a inhibitors

Academic Article
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Overview

authors

  • Janssen, F. J.
  • Baggelaar, M. P.
  • Hummel, J. J. A.
  • Overkleeft, H. S.
  • Cravatt, Benjamin
  • Boger, Dale
  • van der Stelt, M.

publication date

  • December 2015

journal

  • Journal of Medicinal Chemistry  Journal

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.

subject areas

  • Amidohydrolases
  • Databases, Chemical
  • HEK293 Cells
  • Humans
  • Ketones
  • Lipoprotein Lipase
  • Molecular Docking Simulation
  • Oxazoles
  • Protein Binding
  • Pyridines
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC4690813

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.5b01627

PubMed ID

  • 26584396
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Additional Document Info

start page

  • 9742

end page

  • 9753

volume

  • 58

issue

  • 24

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