Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1

Eur J Med Chem. 2018 Mar 10:147:130-149. doi: 10.1016/j.ejmech.2018.01.094. Epub 2018 Feb 2.

Abstract

The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have Ki < 105 nM against human NPP1.

Keywords: Calcific aortic valve disease; NPP1 inhibitor; Quinazoline; Sulfamide.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Phosphoric Diester Hydrolases / metabolism
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Pyrophosphatases / antagonists & inhibitors*
  • Pyrophosphatases / metabolism
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amides
  • Enzyme Inhibitors
  • Piperidines
  • Quinazolines
  • piperidine
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases