ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

Eur J Med Chem. 2017 Feb 15:127:632-642. doi: 10.1016/j.ejmech.2017.01.018. Epub 2017 Jan 12.

Abstract

A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFβ and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.

Keywords: Inhibitor; Protein kinase; Substituted pyrrolo[1,2-b]pyrazoles; Transforming growth factor beta receptor I.

MeSH terms

  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Humans
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human