Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: Improving oral biovailability
- 作者：Yunsong Tong ; Magdalena Przytulinska ; Zhi-Fu Tao ; Jennifer Bouska ; Kent D. Stewart ; Chang Park ; Gaoquan Li ; Akiyo Claiborne ; Peter Kovar ; Zehan Chen ; Philip J. Merta ; Mai-Ha Bui ; Am ; a Olson ; Donald Os
- 关键词：1 ; 4-Dihydroindeno[1 ; 2-c]pyrazole ; Checkpoint kinase 1 inhibitors ; CHK-1 inhibitors ; Sensitizing DNA-damaging agents
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2007
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：15 October 2007
- 卷：17
- 期：20
- 页码：5665-5670
- 文件大小：189 K
摘要
A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.