Discovery of SOAT2 inhibitors from synthetic small molecules

Bioorg Med Chem Lett. 2016 Dec 15;26(24):5899-5901. doi: 10.1016/j.bmcl.2016.11.008. Epub 2016 Nov 5.

Abstract

Synthesis of new functionalized molecules and identification of biofunctional molecules can lead to the development of therapeutic leads and molecular tools for biomedical research. We have recently reported oxa-hetero-Diels-Alder reactions of enones with isatins to provide functionalized spirooxindole tetrahydropyran derivatives. Twenty-one compounds from the spirooxindole tetrahydropyran derivatives and related molecules were screened for inhibition of sterol O-acyltransferase (SOAT) isozymes SOAT1 and SOAT2. Three racemic derivatives inhibited the SOAT2 isozyme with three-fold or better selectivity for SOAT2 than for SOAT1. The enantiomerically enriched forms of the most efficient racemic inhibitor of SOAT2 were further evaluated; one enantiomer inhibited SOAT2 with an IC50 of 1.5μM and was 10-fold more selective for SOAT2 than SOAT1.

Keywords: Hetero-Diels-Alder reaction; Inhibitor; Isozyme; Spirooxindole; Sterol O-acyltransferase; Tetrahydropyran.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Pyrans / chemical synthesis
  • Pyrans / chemistry
  • Pyrans / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Sterol O-Acyltransferase / metabolism
  • Sterol O-Acyltransferase 2
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrans
  • Small Molecule Libraries
  • Sterol O-Acyltransferase
  • sterol O-acyltransferase 1