2 research outputs found
Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding
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-arachidonoylÂglycerol (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
Identification and Development of Biphenyl Substituted Iminosugars as Improved Dual Glucosylceramide Synthase/Neutral Glucosylceramidase Inhibitors
This
work details the evaluation of a number of N-alkylated deoxynojirimycin
derivatives on their merits as dual glucosylceramide synthase/neutral
glucosylceramidase inhibitors. Building on our previous work, we synthesized
a series of d-<i>gluco</i> and l-<i>ido</i>-configured iminosugars N-modified with a variety of
hydrophobic functional groups. We found that iminosugars featuring <i>N</i>-pentyloxyÂmethylaryl substituents are considerably
more potent inhibitors of glucosylceramide synthase than their aliphatic
counterparts. In a next optimization round, we explored a series of
biphenyl-substituted iminosugars of both configurations (d-<i>gluco</i> and l-<i>ido</i>) with
the aim to introduce structural features known to confer metabolic
stability to drug-like molecules. From these series, two sets of molecules
emerge as lead series for further profiling. Biphenyl-substituted l-<i>ido</i>-configured deoxynojirimycin derivatives
are selective for glucosylceramidase and the nonlysosomal glucosylceramidase,
and we consider these as leads for the treatment of neuropathological
lysosomal storage disorders. Their d-<i>gluco</i>-counterparts are also potent inhibitors of intestinal glycosidases,
and because of this characteristic, we regard these as the prime candidates
for type 2 diabetes therapeutics