Design and synthesis of isoquinolines and benzimidazoles as RAF kinase inhibitors

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2264-9. doi: 10.1016/j.bmcl.2011.02.108. Epub 2011 Mar 1.

Abstract

RAF kinase plays a critical role in the RAF-MEK-ERK signaling pathway and inhibitors of RAF could be of use for the treatment of various cancer types. We have designed potent RAF-1 inhibitors bearing novel bicyclic heterocycles as key structural elements for the interaction with the hinge region. In both series exploration of the SAR was focussed on the substitution of the phenyl ring, which binds to the induced fit pocket. Overall, it was confirmed that incorporation of lipophilic substituents was needed for potent Raf inhibition and a number of potent analogues were obtained.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Drug Design
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction
  • Structure-Activity Relationship
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / metabolism

Substances

  • Benzimidazoles
  • Isoquinolines
  • Protein Kinase Inhibitors
  • raf Kinases