Abstract
The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.
MeSH terms
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Alkynes / adverse effects
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Alkynes / chemical synthesis*
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Alkynes / pharmacology
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Binding, Competitive
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Cell Line
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ERG1 Potassium Channel
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Edema / chemically induced
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Edema / drug therapy
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Estradiol
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Ether-A-Go-Go Potassium Channels / drug effects*
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Ether-A-Go-Go Potassium Channels / physiology
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Female
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Humans
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Indenes / adverse effects
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Indenes / chemical synthesis*
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Indenes / pharmacology
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Patch-Clamp Techniques
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Protein Binding
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Pyrazoles / adverse effects
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Pyrazoles / chemical synthesis*
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Pyrazoles / metabolism
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Pyrazoles / pharmacology
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Radioligand Assay
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / metabolism
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Thiophenes / pharmacology
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Uterine Diseases / chemically induced
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Uterine Diseases / drug therapy
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Xenograft Model Antitumor Assays
Substances
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6-((4-methylpiperazin-1-yl)methyl)-3-(5-(3-phenoxyprop-1-ynyl)thiophen-3-yl)-1,4-dihydroindeno(1,2-c)pyrazole
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7-((1H-1,2,4-triazol-1-yl)methyl)-3-(5-(3-(2-methoxyethoxy)prop-1-ynyl)thiophen-3-yl)-1,4-dihydroindeno(1,2-c)pyrazole
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Alkynes
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Antineoplastic Agents
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Indenes
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KCNH2 protein, human
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Pyrazoles
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Thiophenes
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Estradiol
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Receptors, Platelet-Derived Growth Factor
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-2