2,4-Diaminopyrimidine inhibitors of c-Met kinase bearing benzoxazepine anilines
| Autor: | Deborah Galinis, Sheila J. Miknyoczki, Ted L. Underiner, Damaris Rolon-Steele, Jean Husten, Craig A. Zificsak, Thelma S. Angeles, Torsten Herbertz, Mark S. Albom, Bruce D. Dorsey, Laura S. Kocsis, Kevin J. Wells-Knecht, Jay P. Theroff, Lisa D. Aimone, Kelli S. Zeigler, Candace S. Worrell, Rebecca A. Brown, Christine LoSardo, Seetha Murthy, Jennifer Grobelny |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Stereochemistry
medicine.drug_class Metabolite Clinical Biochemistry Substituent Administration Oral Mice Nude Pharmaceutical Science Antineoplastic Agents Carboxamide Biochemistry Chemical synthesis Mice chemistry.chemical_compound In vivo Neoplasms Drug Discovery medicine Animals Humans Protein Kinase Inhibitors Molecular Biology biology Bicyclic molecule Chemistry Organic Chemistry Proto-Oncogene Proteins c-met Xenograft Model Antitumor Assays Pyrimidines Diaminopyrimidine Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:660-663 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2010.12.013 |
| Popis: | Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect