Discovery of novel inhibitors to investigate diacylglycerol lipases and α/β hydrolase domain 16A

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Discovery of novel inhibitors to investigate diacylglycerol lipases and α/β hydrolase domain 16A

Type: Doctoral Thesis
Title: Discovery of novel inhibitors to investigate diacylglycerol lipases and α/β hydrolase domain 16A
Author: Janssen, F.J.
Issue Date: 2016-12-01
Keywords: Serine-hydrolases
Drug-discovery
Medicinal-chemistry
Diacylglycerol-lipases
Endocannabinoids
Neuroinflammation
Obesity
A/b-hydrolase domain16A
PHARC
Abstract: This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease.
Promotor: Supervisor: H.S. Overkleeft Co-Supervisor: M. van der Stelt
Faculty: Science
University: Leiden
Handle: http://hdl.handle.net/1887/44705
 

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