Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors

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• 作者：Edward J. Brnardic ; Robert M. Garbaccio ; Mark E. Fraley ; Edward S. Tasber ; Justin T. Steen ; Kenneth L. Arrington ; Vadim Y. Dudkin ; George D. Hartman ; Steven M. Stirdivant ; Bob A. Drakas ; Keith Rickert
• 关键词：Chk1 kinase ; Pyrazoloquinolinone ; Oncology ; Checkpoint escape ; DNA damage
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 出版时间：1 November 2007
• 年：2007
• 卷：17
• 期：21
• 页码：5989-5994
• 全文大小：465 K

文摘

The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC₅₀ = 3.1 nM).