Discovery of Potent, Selective, and Direct Acid Sphingomyelinase Inhibitors with Antidepressant Activity

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.