1. 5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases
- Author
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Hongjian Zhang, Brian E. Fink, David R. Langley, Harold Mastalerz, Ming Chang, Punit Marathe, Simone Oppenheimer, Dolatrai M. Vyas, Ping Chen, Bogdan Sleczka, John S. Tokarski, Francis Y. Lee, Kenneth J. Leavitt, Johnson Walter Lewis, Wen-Ching Han, Tai W. Wong, Ashvinikumar V. Gavai, Guifen Zhang, Henry Wong, Gregory D. Vite, Tarrant James G, and Derek J. Norris
- Subjects
Insecta ,Molecular model ,Receptor, ErbB-2 ,Stereochemistry ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Chemical synthesis ,Inhibitory Concentration 50 ,Adenosine Triphosphate ,Piperidines ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Pyrroles ,Epidermal growth factor receptor ,Molecular Biology ,chemistry.chemical_classification ,biology ,Triazines ,Chemistry ,Kinase ,Organic Chemistry ,In vitro ,ErbB Receptors ,Enzyme ,Models, Chemical ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Signal transduction ,Neoplasm Transplantation - Abstract
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
- Published
- 2007
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