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
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3T3 Cells
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Animals
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Biological Availability
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CSK Tyrosine-Protein Kinase
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Humans
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Male
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Mice
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Mice, Nude
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyridones / chemical synthesis*
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Pyridones / chemistry
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Rats, Wistar
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
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Receptors, Platelet-Derived Growth Factor / metabolism
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Structure-Activity Relationship
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Transplantation, Heterologous
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Tumor Cells, Cultured
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src-Family Kinases
Substances
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2-(4-(2-diethylaminoethoxy)phenylamino)-8-ethyl-6-phenyl-8H-pyrido(2,3-d)pyrimidin-7-one
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Enzyme Inhibitors
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Pyridones
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Pyrimidines
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Receptors, Fibroblast Growth Factor
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Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human