Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d]pyrimidines: identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors

J Med Chem. 1998 Oct 22;41(22):4365-77. doi: 10.1021/jm980398y.

Abstract

Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.

MeSH terms

  • 3T3 Cells
  • Animals
  • Biological Availability
  • CSK Tyrosine-Protein Kinase
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • src-Family Kinases

Substances

  • 2-(4-(2-diethylaminoethoxy)phenylamino)-8-ethyl-6-phenyl-8H-pyrido(2,3-d)pyrimidin-7-one
  • Enzyme Inhibitors
  • Pyridones
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human