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
| Autor: | Brian G. Hartl, Randy Steinkampf, T C Major, Joan A. Keiser, Tawny K. Dahring, H. D. Hollis Showalter, Gina H. Lu, Alan J. Kraker, Robert L. Panek, Hussein Hallak, Brian L. Batley, Zhipei Wu, Bill J. Roberts, Sylvester Klutchko, Sandra J. Patmore, William L. Elliott, Laura A. Bradford, Wayne D. Klohs, Annette Marian Doherty, James Marino Hamby, Diane H. Boschelli |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Platelet-derived growth factor Pyrimidine Pyridones Transplantation Heterologous Biological Availability Mice Nude Muscle Smooth Vascular CSK Tyrosine-Protein Kinase Mice Structure-Activity Relationship chemistry.chemical_compound Growth factor receptor Drug Discovery Tumor Cells Cultured Animals Humans Receptors Platelet-Derived Growth Factor Enzyme Inhibitors Phosphorylation Rats Wistar biology 3T3 Cells Protein-Tyrosine Kinases Receptors Fibroblast Growth Factor Rats Pyrimidines src-Family Kinases chemistry Biochemistry Enzyme inhibitor Fibroblast growth factor receptor biology.protein Molecular Medicine Drug Screening Assays Antitumor Signal transduction Tyrosine kinase Platelet-derived growth factor receptor |
| Zdroj: | Journal of Medicinal Chemistry. 41:4365-4377 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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