2. Academic Validation
  3. Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding

Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding

  • J Med Chem. 2017 Jan 12;60(1):428-440. doi: 10.1021/acs.jmedchem.6b01482.
Hui Deng 1,  Sander Kooijman 2,  Adrianus M C H van den Nieuwendijk 3,  Daisuke Ogasawara 4,  Tom van der Wel 1,  Floris van Dalen 1,  Marc P Baggelaar 1,  Freek J Janssen 1,  Richard J B H N van den Berg 3,  Hans den Dulk 1,  Benjamin F Cravatt 4,  Herman S Overkleeft 3,  Patrick C N Rensen 2,  Mario van der Stelt 1
Affiliations

Affiliations

  • 1 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
  • 2 Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands.
  • 3 Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
  • 4 Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
PMID: 27992221 DOI: 10.1021/acs.jmedchem.6b01482
Abstract

Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.

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