Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 1

Bioorg Med Chem Lett. 2011 Jan 1;21(1):467-70. doi: 10.1016/j.bmcl.2010.10.113. Epub 2010 Oct 27.

Abstract

The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Checkpoint Kinase 1
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Evaluation, Preclinical
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • pyrazolo(1,5-a)pyrimidine
  • Protein Kinases
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinase 2