2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones. structure-activity relationships against selected tyrosine kinases and in vitro and in vivo anticancer activity
| Autor: | Patrick W. Vincent, Aneesa M. Amar, Gina H. Lu, Diane H. Boschelli, James M. Nelson, Hussein Hallak, Sylvester Klutchko, Donald J. Dykes, Laura A. Bradford, Panek Rl, Chad L. Stoner, Wayne D. Klohs, James M. Hamby, Brian G. Hartl, H. D. Hollis Showalter, Randall W. Steinkampf, Alan J. Kraker, Annette M. Doherty, Billy J. Roberts, Cynthia Shen, William L. Elliott, Terry C. Major, Tawny K. Dahring, Zhipei Wu, Denise L. Driscoll |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Male
medicine.medical_treatment Transplantation Heterologous Molecular Conformation Mice Nude Antineoplastic Agents Pyrimidinones Pharmacology Mice Structure-Activity Relationship In vivo Epidermal growth factor Drug Discovery medicine Tumor Cells Cultured Structure–activity relationship Animals Humans Enzyme Inhibitors Biotransformation Ovarian Neoplasms Platelet-Derived Growth Factor biology Molecular Structure Chemistry Growth factor Autophosphorylation Receptor Protein-Tyrosine Kinases 3T3 Cells Protein-Tyrosine Kinases Rats Fibroblast growth factor receptor biology.protein Molecular Medicine Female Cisplatin Tyrosine kinase Platelet-derived growth factor receptor Cell Division |
| Zdroj: | Journal of medicinal chemistry. 41(17) |
| ISSN: | 0022-2623 |
| Popis: | While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|