Tyrosine Kinase Inhibitors. 19. 6-Alkynamides of 4-Anilinoquinazolines and 4-Anilinopyrido[3,4-d]pyrimidines as Irreversible Inhibitors of the erbB Family of Tyrosine Kinase Receptors
| Autor: | James M. Nelson, Danielle M. Amato, William A. Denny, Patricia J. Harvey, Veronica Sherwood, R. Thomas Winters, David W. Fry, Sylvester R. Klutchko, Jeff B. Smaill, Zhou Hairong, Paul A. Ellis, Hyo Kyung Han, Mary Ann Meade, Gerry Pace, H. D. Hollis Showalter, Tuan P. Tran, William L. Elliott, Billy J. Roberts, Irene W. Althaus, Alexander James Bridges, Andrea J. Gonzales |
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| Rok vydání: | 2006 |
| Předmět: |
Receptor
ErbB-4 Pyrimidine Receptor ErbB-2 Stereochemistry Mice Nude Antineoplastic Agents Mice SCID Receptor tyrosine kinase Cell Line Mice Structure-Activity Relationship chemistry.chemical_compound Pyrimidine analogue Dogs Drug Discovery Quinazoline Animals Humans Phosphorylation chemistry.chemical_classification Aniline Compounds biology Receptor Protein-Tyrosine Kinases Aromatic amine Haplorhini Amides Xenograft Model Antitumor Assays Rats ErbB Receptors Pyrimidines chemistry Biochemistry Epidermoid carcinoma Enzyme inhibitor Alkynes Quinazolines biology.protein Molecular Medicine Tyrosine kinase |
| Zdroj: | Journal of Medicinal Chemistry. 49:1475-1485 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm050936o |
| Popis: | Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI.HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma. |
| Databáze: | OpenAIRE |
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