Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate

J Med Chem. 2010 Jul 22;53(14):5213-28. doi: 10.1021/jm100262j.

Abstract

Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinase C
  • Aurora Kinases
  • Biological Availability
  • Blood Proteins / metabolism
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Female
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Neoplasm Transplantation
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo(4,5-b)pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole
  • Blood Proteins
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Imidazoles
  • Pyridines
  • AURKB protein, human
  • AURKC protein, human
  • Aurka protein, mouse
  • Aurkb protein, mouse
  • Aurkc protein, mouse
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinase C
  • Aurora Kinases
  • Protein Serine-Threonine Kinases