Potency switch between CHK1 and MK2: discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors

Bioorg Med Chem Lett. 2013 May 15;23(10):2863-7. doi: 10.1016/j.bmcl.2013.03.100. Epub 2013 Apr 4.

Abstract

Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.

MeSH terms

  • Checkpoint Kinase 1
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrimidines
  • imidazo(1,2-a)pyrazine
  • imidazo(1,2-c)pyrimidine
  • Protein Kinases
  • MAP-kinase-activated kinase 2
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases