Document Report Card

ID: ALA1135526

Journal: J Med Chem

Title: Discovery of 2-phenylamino-imidazo[4,5-h]isoquinolin-9-ones: a new class of inhibitors of lck kinase.

Authors: Snow RJ, Cardozo MG, Morwick TM, Busacca CA, Dong Y, Eckner RJ, Jacober S, Jakes S, Kapadia S, Lukas S, Panzenbeck M, Peet GW, Peterson JD, Prokopowicz AS, Sellati R, Tolbert RM, Tschantz MA, Moss N.

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.

CiteXplore: 12139450

DOI: 10.1021/jm020113o