Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE)

Eur J Med Chem. 2014 May 22:79:128-42. doi: 10.1016/j.ejmech.2014.03.072. Epub 2014 Mar 26.

Abstract

In an effort to develop novel inhibitors of receptor for advanced glycation end products (RAGE) for the treatment of Alzheimer's disease, a series of pyrazole-5-carboxamides were designed, synthesized and biologically evaluated. Analyses of the extensive structure-activity relationship (SAR) led us to identify a 4-fluorophenoxy analog (40) that exhibited improved in vitro RAGE inhibitory activity and more favorable aqueous solubility than the parent 2-aminopyrimidine, 1. Surface plasmon resonance (SPR) and molecular docking study strongly supported the RAGE inhibitory activity of pyrazole-5-carboxamides. The brain Aβ-lowering effect of 40 is also described.

Keywords: Alzheimer's disease, RAGE inhibitor; Pyrazole-5-carboxamide; RAGE (receptor for advanced glycation end products); SAR (structure–activity relationship).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors
  • Brain
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Peptide Fragments / antagonists & inhibitors
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Surface Plasmon Resonance

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Pyrazoles
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • amyloid beta-protein (1-42)
  • pyrazole-5-carboxamide