Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

详细信息    查看全文

• 作者：Zhen Wang ; Huan Bian ; Sergio G. Bartual ; Wenting Du ; Jinfeng Luo ; Hu Zhao ; Shasha Zhang ; Cheng Mo ; Yang Zhou ; Yong Xu ; Zhengchao Tu ; Xiaomei Ren ; Xiaoyun Lu ; Rolf A. Brekken ; Libo Yao ; Alex N. Bullock ; Jin Su ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 23, 2016
• 年：2016
• 卷：59
• 期：12
• 页码：5911-5916
• 全文大小：422K
• 年卷期：0
• ISSN：1520-4804

文摘

The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a K_d value of 4.7 nM and suppresses its kinase activity with an IC₅₀ value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model.