1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: Extended exploration on phenyl ring substitutions and preliminary ADME/PK studies

详细信息	查看全文 | 推荐本文 |

• 作者：Yunsong Tong ; Akiyo Claiborne ; Magdalena Pyzytulinska ; Zhi-Fu Tao ; Kent D. Stewart ; Peter Kovar ; Zehan Chen ; Robert B. Credo ; Ran Guan ; Philip J. Merta ; et al.
• 关键词：1 ; 4-Dihydroindeno[1 ; 2-c]pyrazoles ; 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：1 July 2007
• 卷：17
• 期：13
• 页码：3618-3623
• 文件大小：169 K

摘要

A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC₅₀ values below 0.3 nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed.