Discovery of 2-Phenylamino-imidazo[4,5-h]isoquinolin-9-ones: A New Class of Inhibitors of Lck Kinase
Journal of Medicinal Chemistry2002Vol. 45(16), pp. 3394–3405
Citations Over TimeTop 18% of 2002 papers
Roger J. Snow, Mario Cardozo, Tina M. Morwick, Carl A. Busacca, Yong Qiang Dong, Robert J. Eckner, Stephen P. Jacober, Scott Jakes, Suresh Kapadia, Susan Lukas, M. J. Panzenbeck, Gregory W. Peet, Jeffrey D. Peterson, Anthony S. Prokopowicz, Rosemarie Sellati, Robert M. Tolbert, Matt A. Tschantz, Neil Moss
Abstract
An imidazo[4,5-h]isoquinolin-7,9-dione (1) was identified as an adenosine 5'-triphosphate competitive inhibitor of lck by high throughput screening. Initial structure-activity relationship studies identified the dichlorophenyl ring and the imide NH as important pharmacophores. A binding model was constructed to understand how 1 binds to a related kinase, hck. These results suggested that removing the gem-dimethyl group and flattening the ring would enhance activity. This was realized by converting 1 to the imidazo[4,5-h]isoquinolin-9-one (20), resulting in an 18-fold improvement in potency against lck and a 50-fold increase in potency in a cellular assay.
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