2. Academic Validation
  3. Chiral disubstituted piperidinyl ureas: a class of dual diacylglycerol lipase-α and ABHD6 inhibitors

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

  • Medchemcomm. 2017 Mar 10;8(5):982-988. doi: 10.1039/c7md00029d.
Hui Deng 1,  Tom van der Wel 1,  Richard J B H N van den Berg 2,  Adrianus M C H van den Nieuwendijk 2,  Freek J Janssen 1,  Marc P Baggelaar 1,  Hermen S Overkleeft 2,  Mario van der Stelt 1
Affiliations

Affiliations

  • 1 Department of Molecular Physiology , Leiden Institute of Chemistry , Leiden University , Leiden , The Netherlands . Email: [email protected].
  • 2 Department of Bio-organic Synthesis , Leiden Institute of Chemistry , Leiden University , Leiden , The Netherlands.
PMID: 30108813 DOI: 10.1039/c7md00029d
Abstract

Inhibitors of diacylglycerol lipases and α,β-hydrolase domain containing protein 6 (ABHD6) are potential leads for the development of therapeutic agents for metabolic and neurodegenerative disorders. Here, we report the enantioselective synthesis and structure activity relationships of triazole ureas featuring chiral, hydroxylated 2-benzylpiperidines as dual inhibitors of DAGLα and ABHD6. The chirality of the carbon bearing the C2 substituent, as well as the position of the hydroxyl (tolerated at C5, but not at C3) has profound influence on the inhibitory activity of both DAGLα and ABHD6, as established using biochemical assays and competitive activity-based protein profiling on mouse brain extracts.

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