Discovery and Optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors

详细信息    查看全文

• 作者：Mingshan Gao ; Lei Duan ; Jinfeng Luo ; Lianwen Zhang ; Xiaoyun Lu ; Yan Zhang ; Zhang Zhang ; Zhengchao Tu ; Yong Xu ; Xiaomei Ren ; Ke Ding
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 25, 2013
• 年：2013
• 卷：56
• 期：8
• 页码：3281-3295
• 全文大小：581K
• 年卷期：v.56,no.8(April 25, 2013)
• ISSN：1520-4804

文摘

Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the enzymatic activity of DDR1, with IC₅₀ values of 6.8 and 7.0 nM, respectively, but were significantly less potent in suppressing the kinase activities of DDR2, Bcr-Abl, and c-Kit. Further study revealed that 7rh bound with DDR1 with a K_d value of 0.6 nM, while it was significantly less potent to the other 455 kinases tested. The S(35) and S(10) selectivity scores of 7rh were 0.035 and 0.008, respectively. The compounds also potently inhibited the proliferation of cancer cells expressing high levels of DDR1 and strongly suppressed cancer cell invasion, adhesion, and tumorigenicity. Preliminary pharmacokinetic studies suggested that they possessed good PK profiles, with oral bioavailabilities of 67.4% and 56.2%, respectively.