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

J Med Chem. 2002 Aug 1;45(16):3394-405. doi: 10.1021/jm020113o.

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.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Binding Sites
  • 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
  • Interleukin-2 / biosynthesis
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Jurkat Cells
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Conformation
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism

Substances

  • 2-(2,6-dichlorophenylamino)-6,7-dimethyl-1,8-dihydroimidazo(4,5-h)isoquinoline-9-one
  • Antibodies
  • CD3 Complex
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-2
  • Isoquinolines
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)