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Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors
Edward J Brnardic1, Robert M Garbaccio, Mark E Fraley
1Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. edward_brnardic@merck.com
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 IC(50)=3.1 nM).
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