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Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity
Open accessAbstract
Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC(50) = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of 1a led to 1c, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC(50) of 1.2 nM in the Src enzymatic assay, an IC(50) of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.
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Metadata
- Authors
- Boschelli, D. H., Ye, F., Wang, Y. D., Dutia, M., Johnson, S. L., Wu, B., Miller, K., Powell, D. W., Yaczko, D., Young, M., Tischler, M., Arndt, K., Discafani, C., Etienne, C., Gibbons, J., Grod, J., Lucas, J., Weber, J. M., & Boschelli, F.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2001-10-17
- Volume
- 44
- Issue
- 23
- Pages
- 3965-3977
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2042794231
- Cited by
- 217
- References
- 0
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- green
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