Discovery of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides as small molecule inhibitors of PCSK9

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3685-3688. doi: 10.1016/j.bmcl.2018.10.029. Epub 2018 Oct 22.

Abstract

A series of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides were identified as small molecule PCSK9 mRNA translation inhibitors. Analogues from this new chemical series, such as 4d and 4g, exhibited improved PCSK9 potency, ADME properties, and in vitro safety profiles when compared to earlier lead structures.

Keywords: Medchem; PCSK9; Parallel synthesis; SAR; Urea.

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism
  • Amides / pharmacology
  • Animals
  • Cell Membrane Permeability / drug effects
  • Crystallography, X-Ray
  • Dogs
  • Humans
  • Inhibitory Concentration 50
  • Madin Darby Canine Kidney Cells
  • Molecular Conformation
  • PCSK9 Inhibitors*
  • Piperidines / chemistry*
  • Proprotein Convertase 9 / metabolism
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Amides
  • PCSK9 Inhibitors
  • Piperidines
  • Protease Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9