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.
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Chemistry, Pharmaceutical / methods*
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Drug Design
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Drug Screening Assays, Antitumor
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ErbB Receptors / chemistry*
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Humans
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Inhibitory Concentration 50
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Insecta
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Models, Chemical
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Neoplasm Transplantation
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Neoplasms / drug therapy*
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Receptor, ErbB-2 / chemistry*
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Triazines / chemical synthesis*
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Triazines / chemistry
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Triazines / pharmacology
Substances
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Antineoplastic Agents
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Piperidines
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Pyrroles
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Triazines
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Adenosine Triphosphate
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ErbB Receptors
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Receptor, ErbB-2