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

Hui Deng, Sander Kooijman, Adrianus M C H van den Nieuwendijk, Daisuke Ogasawara, Tom van der Wel, Floris van Dalen, Marc P Baggelaar, Freek J Janssen, Richard J B H N van den Berg, Hans den Dulk, Benjamin F Cravatt, Herman S Overkleeft, Patrick C N Rensen, Mario van der Stelt

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)428-440
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number1
Publication statusPublished - 12 Jan 2017


  • Animals
  • Eating
  • Enzyme Inhibitors/pharmacology
  • Fasting
  • HEK293 Cells
  • Humans
  • Lipoprotein Lipase/antagonists & inhibitors
  • Mice
  • Structure-Activity Relationship
  • Triazoles/chemistry
  • Urea/chemistry


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