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 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): A Novel Oncology Therapeutic Agent
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 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): A Novel Oncology Therapeutic Agent
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DOI：
10.1021/jm201449n
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发表时间：
2012-01-26
影响因子：
7.3
通讯作者：
Ruggeri, Bruce A.
中科院分区：
文献类型：
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作者：
Hudkins, Robert L.;Becknell, Nadine C.;Ruggeri, Bruce A.
大量证据支持使用抗血管生成抑制剂作为一种策略来阻断或减弱肿瘤诱导的血管生成，并抑制各种实体和血液肿瘤的原发和转移肿瘤生长。鉴于肿瘤在生长和扩散的不同阶段对不同细胞因子和生长因子的需求，最佳的抗血管生成治疗需要抑制多个、互补和非冗余的血管生成靶点。11-(2-Methylpropyl)-12，13-dihydro-2-methy-8-(pyrimidin-2-ylamino)-4H-indazolo[5，4-a]pyrrolo[3，4-c]carbazol-4-one(11b，CEP-11981)是一种有效的多靶点(Tie-2、VEGFR1、2、3和FGFR1)的口服活性抑制物，在肿瘤血管生成和血管维持中具有重要的和非多余的作用。本文概述了11b的设计策略、合成、生化和药理学概况，它完成了第一阶段临床评估安全性和药代动力学，允许启动概念验证研究。
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-methy-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.