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

Christopher, John A.; Bamborough, Paul; Alder, Catherine; Campbell, Amanda; Cutler, Geoffrey J.; Down, Kenneth; Hamadi, Ahmed M.; Jolly, Adrian M.; Kerns, Jeffrey K.; Lucas, Fiona S.; Mellor, Geoffrey W.; Miller, David D.; Morse, Mary A.; Pancholi, Kiritkant D.; Rumsey, William; Solanke, Yemisi E.; Williamson, Rick

doi:10.1021/jm9000117.s001

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

journal contribution

posted on 2009-05-14, 00:00 authored by John A. Christopher, Paul Bamborough, Catherine Alder, Amanda Campbell, Geoffrey J. Cutler, Kenneth Down, Ahmed M. Hamadi, Adrian M. Jolly, Jeffrey K. Kerns, Fiona S. Lucas, Geoffrey W. Mellor, David D. Miller, Mary A. Morse, Kiritkant D. Pancholi, William Rumsey, Yemisi E. Solanke, Rick Williamson

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.