SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1744-8. doi: 10.1016/j.bmcl.2010.01.087. Epub 2010 Jan 21.

Abstract

The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Cell Line, Tumor
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Pregnane X Receptor
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / metabolism
  • Receptors, Steroid / genetics*
  • Receptors, Steroid / metabolism
  • Structure-Activity Relationship
  • Transcriptional Activation*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Pregnane X Receptor
  • Protein Kinase Inhibitors
  • Receptors, Steroid
  • Cytochrome P-450 CYP3A
  • Receptor, IGF Type 1