Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action

Multiple studies have confirmed that acid sphingomyelinase
(ASM)
activity is associated with depression. The discovery of direct inhibitors
against ASM is of great significance for exploring antidepressants
and their mechanisms of action. Herein, a series of novel phenylpyrazole
analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 =
0.87 μM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved
in multiple antidepressant mechanisms of action, which were associated
with a decline of ceramide, including increasing the Bcl-2/Bax ratio
and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating
oxidative stress, reducing the levels of proinflammatory cytokines
such as TNF-α, IL-1β, and IL-6, and elevating 5-HT levels
in the brains of mice, respectively. These meaningful results reveal
for the first time that direct inhibitors exhibit remarkable antidepressant
effects in the CUMS-induced mouse model through multiple mechanisms
of antidepressant action.