Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity

J Med Chem. 2008 Oct 9;51(19):5897-900. doi: 10.1021/jm800832q. Epub 2008 Sep 3.

Abstract

We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Pregnane X Receptor
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridones / administration & dosage*
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptors, Steroid / drug effects
  • Receptors, Steroid / metabolism
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo(d)imidazol-2-yl)pyridin-2(1H)-one
  • Antineoplastic Agents
  • Benzimidazoles
  • Cytochrome P-450 CYP3A Inhibitors
  • Pregnane X Receptor
  • Protein Kinase Inhibitors
  • Pyridones
  • Receptors, Steroid
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Receptor, IGF Type 1