Discovery of 2,3'-diindolylmethanes as a novel class of PCSK9 modulators

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2345-2348. doi: 10.1016/j.bmcl.2019.06.014. Epub 2019 Jun 12.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR). Anti-PCSK9 agents have been approved for the treatment of hypercholesterolemia. We recently discovered a series of small-molecule PCSK9 modulators that contains a relatively small pharmacophore of 2,3'-diindolylmethane with molecular weights around only 250. These molecules can significantly lower the amount of PCSK9 protein in a cell-based phenotypic assay. Our SAR studies yielded compound 16 with a IC50-value of 200 nM. No obvious cytotoxicity was observed at concentrations below 50 µM.

Keywords: Diindolylmethane; Hypercholesterolemia; Indole; LDLR; PCSK9.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hep G2 Cells
  • Humans
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / metabolism
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • PCSK9 Inhibitors*
  • Proprotein Convertase 9 / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Indoles
  • PCSK9 Inhibitors
  • Small Molecule Libraries
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • 3,3'-diindolylmethane