Bioorganic & medicinal chemistry letters · 2007
Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: improving oral biovailability.
СтатьяНазвание и аннотация: Перевод в очереди
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Tong Yunsong, Przytulinska Magdalena, Tao Zhi-Fu, Bouska Jennifer, Stewart Kent D, Park Chang, Li Gaoquan, Claiborne Akiyo, Kovar Peter, Chen Zehan, Merta Philip J, Bui Mai-Ha, Olson Amanda, Osterling Donald, Zhang Haiying, Sham Hing L, Rosenberg Saul H, Sowin Thomas J, Lin Nan-Horng
Аннотация
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.