Balancing oral exposure with Cyp3A4 inhibition in benzimidazole-based IGF-IR inhibitors

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4075-80. doi: 10.1016/j.bmcl.2008.05.104. Epub 2008 Jun 21.

Abstract

3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Administration, Oral
  • Area Under Curve
  • Benzimidazoles / pharmacology*
  • Chemistry, Pharmaceutical / methods
  • Cytochrome P-450 CYP3A / chemistry
  • Cytochrome P-450 CYP3A Inhibitors*
  • Drug Design
  • Fluorine / chemistry
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Nitrogen / chemistry
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / chemistry
  • Somatomedins / chemistry
  • Thymidine / chemistry

Substances

  • Benzimidazoles
  • Cytochrome P-450 CYP3A Inhibitors
  • Somatomedins
  • Fluorine
  • Adenosine Triphosphate
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Receptor, IGF Type 1
  • Nitrogen
  • Thymidine