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 CB<sub>1</sub> 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 CB<sub>1</sub>-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