Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors

…, RM Garbaccio, ME Fraley, ES Tasber, JT Steen…

Index: Brnardic, Edward J.; Garbaccio, Robert M.; Fraley, Mark E.; Tasber, Edward S.; Steen, Justin T.; Arrington, Kenneth L.; Dudkin, Vadim Y.; Hartman, George D.; Stirdivant, Steven M.; Drakas, Bob A.; Rickert, Keith; Walsh, Eileen S.; Hamilton, Kelly; Buser, Carolyn A.; Hardwick, James; Tao, Weikang; Beck, Stephen C.; Mao, Xianzhi; Lobell, Robert B.; Sepp-Lorenzino, Laura; Yan, Youwei; Ikuta, Mari; Munshi, Sanjeev K.; Kuo, Lawrence C.; Kreatsoulas, Constantine Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, # 21 p. 5989 - 5994

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Citation Number: 30

Abstract

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).