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

• Published in: Journal of medicinal chemistry Vol. 41; no. 22; pp. 4365 - 4377
• Main Authors: Boschelli, Diane H, Wu, Zhipei, Klutchko, Sylvester R, Showalter, H. D. Hollis, Hamby, James M, Lu, Gina H, Major, Terry C, Dahring, Tawny K, Batley, Brian, Panek, Robert L, Keiser, Joan, Hartl, Brian G, Kraker, Alan J, Klohs, Wayne D, Roberts, Bill J, Patmore, Sandra, Elliott, William L, Steinkampf, Randy, Bradford, Laura A, Hallak, Hussein, Doherty, Annette M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.10.1998; Amer Chemical Soc
• Subjects: 3T3 Cells; Animals; Antineoplastic agents; Biological and medical sciences; Biological Availability; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; General aspects; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Nude; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Pharmacology & Pharmacy; Pharmacology. Drug treatments; 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; Science & Technology; src-Family Kinases; Structure-Activity Relationship; Transplantation, Heterologous; Tumor Cells, Cultured; SIGNAL-TRANSDUCTION; SIMIAN SARCOMA-VIRUS; ANGIOGENESIS; ANALOGS; PHENYLAMINO-PYRIMIDINE PAP; BINDING-SITE INHIBITORS; DERIVATIVES; CANCER; AUTOPHOSPHORYLATION; FAMILY; Antineoplastic agent; Cell proliferation; Fibroblast growth factor; Nitrogen heterocycle; Lactam; Signal transduction; Structure activity relation; Bicyclic compound; Inhibition; Chemical synthesis; Protein-tyrosine kinase; Tumor cell; Platelet derived growth factor; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Aminoether; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; C-Onc gene; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980398y

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.