Hit to lead studies on (hetero)arylpyrimidines--agonists of the canonical Wnt-beta-catenin cellular messaging system

Bioorg Med Chem Lett. 2010 Jan 1;20(1):366-70. doi: 10.1016/j.bmcl.2009.10.093. Epub 2009 Oct 25.

Abstract

A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone.

MeSH terms

  • Animals
  • Bone Development / drug effects
  • Cell Line, Tumor
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Recombinant Fusion Proteins / agonists
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Skull / metabolism
  • Wnt Proteins / agonists
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin / agonists
  • beta Catenin / metabolism*

Substances

  • DKK1 protein, human
  • Imidazoles
  • Intercellular Signaling Peptides and Proteins
  • Pyrimidines
  • Recombinant Fusion Proteins
  • WNT3A protein, human
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3