Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model

Eur J Med Chem. 2018 May 10;151:389-400. doi: 10.1016/j.ejmech.2018.03.065. Epub 2018 Mar 27.

Abstract

Acid sphingomyelinase (ASM) has been shown to be involved in many physiological processes, emerging to be a promising drug target. In this study, we constructed a ligand-based pharmacophore model of ASM inhibitors and applied this model to optimize the lead compound α-mangostin, a known inhibitor of ASM. 23 compounds were designed and evaluated in vitro for ASM inhibition, of these, 10 compounds were found to be more potent than α-mangostin. This high hit ratio confirmed that the presented model is very effective and practical. The most potent hit, 1c, was found to selectively and competitively inhibit the enzyme and inhibit the generation of ceramide in a dose-dependent manner. Furthermore, 1c showed favorable anti-apoptosis and anti-inflammatory activity. Interactions with key residues and the Zn2+ cofactor of 1c were found by docking simulation. These results provide promising leads and important guidance for further development of efficient ASM inhibitors and drug candidates.

Keywords: Acid sphingomyelinase; Anti-apoptosis; Anti-inflammatory; Inhibitors; Pharmacophore model.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Apoptosis / drug effects
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Ceramides / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Ligands
  • Mice
  • Molecular Docking Simulation
  • NIH 3T3 Cells
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
  • Sphingomyelin Phosphodiesterase / metabolism

Substances

  • Anti-Inflammatory Agents
  • Benzamides
  • Ceramides
  • Enzyme Inhibitors
  • Ligands
  • Sphingomyelin Phosphodiesterase