Discovery of 2-Phenylamino-imidazo[4,5-h]isoquinolin-9-ones:  A New Class of Inhibitors of Lck Kinase

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 co...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-08, Vol.45 (16), p.3394-3405
Main Authors: Snow, Roger J, Cardozo, Mario G, Morwick, Tina M, Busacca, Carl A, Dong, Yong, Eckner, Robert J, Jacober, Stephen, Jakes, Scott, Kapadia, Suresh, Lukas, Susan, Panzenbeck, Maret, Peet, Gregory W, Peterson, Jeffrey D, Prokopowicz, Anthony S, Sellati, Rosemarie, Tolbert, Robert M, Tschantz, Matt A, Moss, Neil
Format: Article
Language:English
Subjects:
Animals
Antibodies - pharmacology
Binding Sites
Biological and medical sciences
CD3 Complex - immunology
Crystallography, X-Ray
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Female
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Immunomodulators
Interleukin-2 - biosynthesis
Isoquinolines - chemical synthesis
Isoquinolines - chemistry
Isoquinolines - pharmacology
Jurkat Cells
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - antagonists & inhibitors
Medical sciences
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Structure-Activity Relationship
T-Lymphocytes - drug effects
T-Lymphocytes - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020113o