Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors

Bioorg Med Chem Lett. 2002 Oct 7;12(19):2767-70. doi: 10.1016/s0960-894x(02)00525-5.

Abstract

We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.

MeSH terms

  • Endothelial Growth Factors / antagonists & inhibitors
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / pharmacology
  • Mitogens / antagonists & inhibitors
  • Mitogens / pharmacology
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Mitogens
  • Pyrazoles
  • Pyrimidines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor Receptor-2