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Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro- N 2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)- N 4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials

Marsilje, Thomas and Pei, Wei and Lu, Wenshuo and Uno, Tetsuo and Jin, Yunho and Jiang, Tao and Kim, Sungjoon and Li, Nanxin and Sarkisova, Yelena and Steffy, Auzon and Culazzo, Annemarie and Kasibhatla, Shailaja and Joseph, Sean and Kim, Young and Tuntland, Tove and Cui, Xiaoming and Li, Jie and Gordon, William and Richmond, Wendy and Chang, Hsiao-Yen and Groessl, Todd and He, You-Qun and Liu, Bo and Fangxian, Sun and Phimister, Andrew and Aycinena, Juan and Bursulaya, Badry and Lee, Christian and Seidel, Martin and Harris, Jennifer and Michellys, Pierre (2013) Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro- N 2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)- N 4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. Journal of Medicinal Chemistry, 56 (14). pp. 5675-5690. ISSN 0022-2623

Abstract

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients. © 2013 American Chemical Society.

Item Type: Article
Date Deposited: 01 Dec 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/9239

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