Synthesis and Biological Profile of the pan-Vascular Endothelial Growth Factor Receptor/Tyrosine Kinase with Immunoglobulin and Epidermal Growth Factor-Like Homology Domains 2 (VEGF-R/TIE-2) Inhibitor

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• 作者：Robert L. Hudkins ; Nadine C. Becknell ; Allison L. Zulli ; Ted L. Underiner ; Thelma S. Angeles ; Lisa D. Aimone ; Mark S. Albom ; Hong Chang ; Sheila J. Miknyoczki ; Kathryn Hunter ; Susan Jones-Bolin ; Hugh Zhao ; Edward R. Bacon ; John P. Mallamo ; Mark A. Ator ; Bruce A. Ruggeri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：903-913
• 全文大小：432K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.