Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4591-6. doi: 10.1016/j.bmcl.2013.06.031. Epub 2013 Jun 20.

Abstract

The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.

Keywords: CSF-1R; Inhibitor; Kinase.

MeSH terms

  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology
  • Aminoquinolines / toxicity*
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Aniline Compounds / toxicity*
  • Animals
  • Cardiovascular System / drug effects*
  • Cells, Cultured
  • Dogs
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity*
  • Guinea Pigs
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Heterocyclic Compounds, 2-Ring / toxicity*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Myocytes, Cardiac / drug effects
  • Rats
  • Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*

Substances

  • AZ683
  • AZD7507
  • Aminoquinolines
  • Aniline Compounds
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Receptor, Macrophage Colony-Stimulating Factor