Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors: SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one

Bioorg Med Chem Lett. 2010 May 15;20(10):3182-5. doi: 10.1016/j.bmcl.2010.03.057. Epub 2010 Mar 27.

Abstract

A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Humans
  • Mice
  • Mice, Nude
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacokinetics
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology
  • Rats
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • BMS 536924
  • BMS 577098
  • Benzimidazoles
  • Cytochrome P-450 CYP3A Inhibitors
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridones
  • benzimidazole
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Receptor, IGF Type 1