| Autor: |
Wissner, A., Overbeek, E., Reich, M. F., Floyd, M. B., Johnson, B. D., Mamuya, N., Rosfjord, E. C., Discafani, C., Davis, R., Shi, X., Rabindran, S. K., Gruber, B. C., Ye, F., Hallett, W. A., Nilakantan, R., Shen, R., Wang, Y.-F., Greenberger, L. M., Tsou, H.-R. |
| Zdroj: |
Journal of Medicinal Chemistry; January 2003, Vol. 46 Issue: 1 p49-63, 15p |
| Abstrakt: |
A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer. |
| Databáze: |
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