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5-[5-氟-2-氧代-1,2-二氢吲哚-(3Z)-基亚甲基]-2,4-二甲基-1H-吡咯-3-羧酸(2-二乙氨基乙基)酰胺的发现，一种靶向血管内皮生长因子和血小板衍生生长因子受体酪氨酸激酶的新型酪氨酸激酶抑制剂。

Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.

作者信息

Sun Li, Liang Chris, Shirazian Sheri, Zhou Yong, Miller Todd, Cui Jean, Fukuda Juri Y, Chu Ji-Yu, Nematalla Asaad, Wang Xueyan, Chen Hui, Sistla Anand, Luu Tony C, Tang Flora, Wei James, Tang Cho

机构信息

SUGEN, Inc., 230 E. Grand Avenue, South San Francisco, California 94080, USA.

出版信息

J Med Chem. 2003 Mar 27;46(7):1116-9. doi: 10.1021/jm0204183.

DOI:10.1021/jm0204183
PMID:12646019
Abstract

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.

摘要

为了改善吲哚啉 - 2 - 酮的抗肿瘤特性并优化其药学性质，包括溶解度和蛋白结合性，设计并合成了许多不同的碱性和弱碱性类似物。5 - [5 - 氟 - 2 - 氧代 - 1,2 - 二氢吲哚 - (3Z) - 亚甲基甲基] - 2,4 - 二甲基 - 1H - 吡咯 - 3 - 羧酸(2 - 二乙氨基乙基)酰胺(12b或SU11248)在生化和细胞水平上对VEGF - R2和PDGF - Rβ酪氨酸激酶的效力、溶解度、蛋白结合性和生物利用度方面显示出最佳的总体特征。12b目前正处于治疗癌症的I期临床试验阶段。

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