Discovery of the selective sphingomyelin synthase 2 inhibitors with the novel structure of oxazolopyridine

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3511-3515. doi: 10.1016/j.bmcl.2017.05.074. Epub 2017 May 25.

Abstract

Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compound D2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative molecules QY4 and QY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors.

Keywords: Anti-atherosclerosis; Oxazolopyridine; Selective inhibitor; Sphingomyelin synthase 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Molecular Docking Simulation
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism
  • Oxazoles / chemistry
  • Oxazoles / pharmacology
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors*
  • Transferases (Other Substituted Phosphate Groups) / chemistry
  • Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

  • Enzyme Inhibitors
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Oxazoles
  • Pyridines
  • SGMS1 protein, human
  • Transferases (Other Substituted Phosphate Groups)