Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors

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).

The optimization of potency for a pyrazoloquinolinone class of Chk1 kinase inhibitors is described.Figure optionsDownload as PowerPoint slide