Discovery of 6-Aryl-7-alkoxyisoquinoline Inhibitors of IκB Kinase-β (IKK-β)

The identification and progression of a potent and selective series of isoquinoline inhibitors of IκB kinase-β (IKK-β) are described. Hit-generation chemistry based on IKK-β active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-α.