Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

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• 作者：Paul A. Renhowe ; Sabina Pecchi ; Cynthia M. Shafer ; Timothy D. Machajewski ; Elisa M. Jazan ; Clarke Taylor ; William Antonios-McCrea ; Christopher M. McBride ; Kelly Frazier ; Marion Wiesmann ; Gena R. Lapoi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 22, 2009
• 年：2009
• 卷：52
• 期：2
• 页码：278-292
• 全文大小：302K
• 年卷期：v.52,no.2(January 22, 2009)
• ISSN：1520-4804

文摘

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRβ with IC₅₀ values <0.1 μM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.