AI Article Synopsis
- Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a novel solubilizing group showed better performance than previous versions.
- A new method was created for the parallel synthesis of C-4 analogs featuring this solubilizing group.
- In tests on tumor models, the C-4 aminofluorobenzylindazole, identified as compound 1c, demonstrated superior antitumor effectiveness, likely due to improved binding to the ATP binding pocket.
Article 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.
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| http://dx.doi.org/10.1016/j.bmcl.2007.06.019 | DOI Listing |
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