2146 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
Letters
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Totzke, F.; Marme´, D. PTK787/ZK 222584, a novel and potent
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with C-7 basic side chains: design and structure activity relationship
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B.; Rastinejad, F.; Marx, M. A.; Schaeffer, T.; Whalen, P. M.;
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J. P.; Hudkins, R. L. A new class of potent vascular endothelial
growth factor receptor tyrosine kinase inhibitors: structure-activity
relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)-
indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the identification of
CEP-5214 and its dimethylglycine ester prodrug clinical candidate
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Kendrew, J.; Hennequin, L. F.; Valentine, P. J.; Barry, S. T.; Brave,
S. R.; Smith, N. R.; James, N. H.; Dukes, M.; Curwen, J. O.; Chester,
R.; Jackson, J. A.; Boffey, S. J.; Kilburn, L. L.; Barnett, S.; Richmond,
G. H. P.; Wadsworth, P. F.; Walker, M.; Bigley, A. L.; Taylor, S.
T.; Cooper, L.; Beck, S.; Jurgensmeier, J. M.; Ogilvie, D. J.
AZD2171: A highly potent, orally bioavailable, Vascular Endothelial
Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the treatment
of Cancer. Cancer Res. 2005, 65, 4389-4400.
Figure 2. Structure of 21.
an orally active compound in the H3396 xenograft model of
human breast carcinoma, demonstrating almost complete tumor
growth stasis during the dosing period. On the basis of its
excellent enzymatic potency against VEGFR-2, good kinase
selectivity profile, and acceptable safety profile, compound 12
was considered as a candidate for further development and its
prodrug formation was considered to improve pharmaceutics
properties.
Acknowledgment. We thank George Trainor and Robert
Kramer for scientific advice, and the Discovery analytical
sciences for compound characterization.
Supporting Information Available: Characterization data for
compounds 1-16. Full experimental details and the characterization
data for compound 12. This material is available free of charge on
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