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

• Published in: Journal of medicinal chemistry Vol. 50; no. 9; pp. 2011 - 2029
• Main Authors: Dinges, Jürgen, Albert, Daniel H, Arnold, Lee D, Ashworth, Kimba L, Akritopoulou-Zanze, Irini, Bousquet, Peter F, Bouska, Jennifer J, Cunha, George A, Davidsen, Steven K, Diaz, Gilbert J, Djuric, Stevan W, Gasiecki, Alan F, Gintant, Gary A, Gracias, Vijaya J, Harris, Christopher M, Houseman, Kathryn A, Hutchins, Charles W, Johnson, Eric F, Li, Hu, Marcotte, Patrick A, Martin, Ruth L, Michaelides, Michael R, Nyein, Michelle, Sowin, Thomas J, Su, Zhi, Tapang, Paul H, Xia, Zhiren, Zhang, Henry Q
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 03-05-2007
• Subjects: Alkynes - adverse effects; Alkynes - chemical synthesis; Alkynes - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Binding, Competitive; Biological and medical sciences; Cell Line; Edema - chemically induced; Edema - drug therapy; ERG1 Potassium Channel; Estradiol; Ether-A-Go-Go Potassium Channels - drug effects; Ether-A-Go-Go Potassium Channels - physiology; Female; General aspects; Humans; Indenes - adverse effects; Indenes - chemical synthesis; Indenes - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Models, Molecular; Patch-Clamp Techniques; Pharmacology. Drug treatments; Protein Binding; Pyrazoles - adverse effects; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Pyrazoles - pharmacology; Radioligand Assay; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - metabolism; Thiophenes - pharmacology; Uterine Diseases - chemically induced; Uterine Diseases - drug therapy; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Xenograft Model Antitumor Assays; Antineoplastic agent; Acetylenic compound; Angiogenic factor; Nitrogen heterocycle; Cytotoxicity; Fibrosarcoma; Breast carcinoma; Thiophene derivatives; Signal transduction; Structure activity relation; Mammary gland; Inhibition; Chemical synthesis; Protein-tyrosine kinase; Tumor cell; Platelet derived growth factor; Human; Enzyme; Transferases; Oral administration; Enzyme inhibitor; Malignant tumor; In vitro; Mammary gland diseases; In vivo; Chemotherapy; Sulfur heterocycle; Experimental disease; Growth factor receptor; Side chain; Vascular endothelium growth factor; Cell line; Treatment; Animal; Triazole derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061223o

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 μM 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.