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

  • J Med Chem. 2020 Feb 13;63(3):961-974. doi: 10.1021/acs.jmedchem.9b00739.
Kan Yang  1  2 ,  Jinying Yu  1 ,  Keyi Nong  1 ,  Youzhi Wang  1 ,  Ao Niu  1 ,  Wenlu Chen  1 ,  Jibin Dong  3 ,  Jinxin Wang  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy , China Pharmaceutical University , Nanjing 210009 , China.
  • 2. Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences , Hebei University , Baoding 071002 , China.
  • 3. Department of Biochemistry, School of Pharmacy , Fudan University , Shanghai 201203 , China.
PMID: 31944697 DOI: 10.1021/acs.jmedchem.9b00739
Abstract

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.

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