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Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)
Open accessAbstract
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.
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Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00788 · Cited by 588
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Metadata
- Authors
- 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.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2002-12-02
- Volume
- 46
- Issue
- 1
- Pages
- 49-63
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2074730236
- Cited by
- 264
- References
- 0
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2). https://app.cochat.ai/papers/10.1021/jm020241c
- The paper
- 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. (2003). Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2). Journal of Medicinal Chemistry. https://doi.org/10.1021/jm020241c
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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