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

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 <b>38</b> (DH376) with picomolar activity. Compound <b>38</b> temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB₁-receptor inverse agonists. This was mirrored by <b>39</b> (DO34) but also by the negative control compound <b>40</b> (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets