1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.

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.

• Authors: Jürgen Dinges, Daniel H Albert, Lee D Arnold, Kimba L Ashworth, Irini Akritopoulou-Zanze, Peter F Bousquet, Jennifer J Bouska, George A Cunha, Steven K Davidsen, Gilbert J Diaz, Stevan W Djuric, Alan F Gasiecki, Gary A Gintant, Vijaya J Gracias, Christopher M Harris, Kathryn A Houseman, Charles W Hutchins, Eric F Johnson, Hu Li, Patrick A Marcotte, Ruth L Martin, Michael R Michaelides, Michelle Nyein, Thomas J Sowin, Zhi Su, Paul H Tapang, Zhiren Xia, Henry Q Zhang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 9 Pg. 2011-29 (May 03 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17425296 (Publication Type: Journal Article)

Chemical References

• 6-((4-methylpiperazin-1-yl)methyl)-3-(5-(3-phenoxyprop-1-ynyl)thiophen-3-yl)-1,4-dihydroindeno(1,2-c)pyrazole
• 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
• Alkynes
• Antineoplastic Agents
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• Indenes
• KCNH2 protein, human
• Pyrazoles
• Thiophenes
• Estradiol
• Receptors, Platelet-Derived Growth Factor
• Receptors, Vascular Endothelial Growth Factor
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Alkynes (adverse effects, chemical synthesis, pharmacology)
• Animals
• Antineoplastic Agents (adverse effects, chemical synthesis, pharmacology)
• Binding, Competitive
• Cell Line
• ERG1 Potassium Channel
• Edema (chemically induced, drug therapy)
• Estradiol
• Ether-A-Go-Go Potassium Channels (drug effects, physiology)
• Female
• Humans
• Indenes (adverse effects, chemical synthesis, pharmacology)
• Mice
• Mice, Inbred BALB C
• Models, Molecular
• Patch-Clamp Techniques
• Protein Binding
• Pyrazoles (adverse effects, chemical synthesis, metabolism, pharmacology)
• Radioligand Assay
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship
• Thiophenes (chemical synthesis, metabolism, pharmacology)
• Uterine Diseases (chemically induced, drug therapy)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
• Xenograft Model Antitumor Assays