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

ABSTRACT: Inhibitors of diacylglycerol lipases and ?,?-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 DAGL? 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 DAGL? and ABHD6, as established using biochemical assays and competitive activity-based protein profiling on mouse brain extracts.

SUBMITTER: Deng H

PROVIDER: S-EPMC6071720 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Deng Hui H van der Wel Tom T van den Berg Richard J B H N RJBHN van den Nieuwendijk Adrianus M C H AMCH Janssen Freek J FJ Baggelaar Marc P MP Overkleeft Hermen S HS van der Stelt Mario M

MedChemComm 20170310 5

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 a ...[more]

PMID: 30108813

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