Author/Authors :
Harold Mastalerz، نويسنده , , Ming Chang، نويسنده , , Ping Chen، نويسنده , , Brian E. Fink، نويسنده , , Ashvinikumar Gavai، نويسنده , , Wen-Ching Han، نويسنده , , Walter Johnson، نويسنده , , David Langley، نويسنده , , Francis Y. Lee، نويسنده , , Kenneth Leavitt، نويسنده , , Punit Marathe، نويسنده , , Derek Norris، نويسنده , , Simone Oppenheimer، نويسنده , , Bogdan Sleczka، نويسنده , , James Tarrant، نويسنده , , John S. Tokarski، نويسنده , , Gregory D. Vite، نويسنده , , Dolatrai M. Vyas، نويسنده , , Henry Wong، نويسنده , , Tai W. Wong، نويسنده , , et al.، نويسنده ,
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.
Keywords :
EGFR , HER2 , Pyrrolotriazine , kinase inhibitor
