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 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.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Roger J
RJ
Snow
Mario G
MG
Cardozo
Tina M
TM
Morwick
Carl A
CA
Busacca
Yong
Y
Dong
Robert J
RJ
Eckner
Stephen
S
Jacober
Scott
S
Jakes
Suresh
S
Kapadia
Susan
S
Lukas
Maret
M
Panzenbeck
Gregory W
GW
Peet
Jeffrey D
JD
Peterson
Anthony S
AS
Prokopowicz
Rosemarie
R
Sellati
Robert M
RM
Tolbert
Matt A
MA
Tschantz
Neil
N
Moss
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001665:Binding Sites; D017252:CD3 Complex / Q000276:immunology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
C463491:2-(2,6-dichlorophenylamino)-6,7-dimethyl-1,8-dihydroimidazo(4,5-h)isoquinoline-9-one; D000906:Antibodies; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D007546:Isoquinolines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)