Abstract
A series of (6,7-dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines has been optimized to preserve both potent kinase inhibition activity against the angiogenesis target, the receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to improve the broad tumor cell antiproliferative activity of these compounds. This series culminates in the discovery of 17 (JNJ-10198409), a compound with anti-PDGFR-beta kinase activity (IC(50)=0.0042 microM) and potent antiproliferative activity in six of eight human tumor cell lines (IC(50) < 0.033 microM).
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Becaplermin
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Cell Line
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Cell Line, Tumor
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Endothelium, Vascular / drug effects
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Humans
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Indans / chemical synthesis*
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Indans / pharmacology
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Inhibitory Concentration 50
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Platelet-Derived Growth Factor / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins c-sis
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacology
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
Substances
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(6,7-dimethoxy-2,4-dihydroindeno(1,2-c)pyrazol-3-yl)(3-fluorophenyl)amine
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Antineoplastic Agents
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Indans
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Pyrazoles
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Becaplermin
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Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor