Recent studies on sphingolipids suggest that acid sphingomyelinase (ASM), which plays a central role in the pathogenesis of major depression, is emerging to be a novel target for developing antidepressants. Herein we first described the design, synthesis, and biological evaluation of hydroxamic acid-based direct inhibitors of ASM with the effort of validating their antidepressant effects in vivo. As a result, a series of novel ASM inhibitors were developed using a structure-based approach. Our studies demonstrated that the administration of 21b improved depression-like behaviors of rats. Importantly, this positive result was relevant to the inhibition of ASM and the increasing neurogenesis in hippocampus. To the best of our knowledge, this is the first time that direct inhibitors of ASM were developed to support the possibility of ASM as a potential therapeutic target for depression.
Acid sphingomyelinase (ASM), which regulates sphingolipid
metabolism
and lipid signaling, has been considered as a new potential target
for the treatment of atherosclerosis. In this study, a series of benzene-heterocyclic-based
ASM inhibitors were rationally designed, synthesized, and screened
for the first time. As a result, some compounds showed favorable inhibitory
activity against recombinant human ASM. The detailed SARs are also
discussed. Compound 4i revealed good pharmacokinetic
data and in vivo inhibitory activity against ASM
by reducing the level of ceramide in mice plasma and liver. Pharmacodynamic
studies confirmed that 4i could lessen lipid plaques
in the aortic arch and aorta and reduce plasma ceramide concentration
and Ox-LDL levels. Moreover, 4i was found to significantly
decrease LPS-induced and Ox-LDL-induced cell inflammation by regulating
the levels of ceramide and sphingomyelin. Overall, this study preliminarily
demonstrates that ASM may be an effective target against atherosclerosis
for the first time.
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