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

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• 作者：J&uuml ; rgen 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.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 3, 2007
• 年：2007
• 卷：50
• 期：9
• 页码：2011 - 2029
• 全文大小：390K
• 年卷期：v.50,no.9(May 3, 2007)
• ISSN：1520-4804

文摘

The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains isdescribed. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oralactivity 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 growthmodel (tumor growth inhibition = 90% at 25 mg/kg·day po). The compound was docked into a homologymodel of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improveits 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 M in the hERG patch clamp assay. The selectivityprofile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors withlow nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.