Optimization of 2-phenylaminoimidazo[4,5-h]isoquinolin-9-ones: orally active inhibitors of lck kinase.
The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.
Goldberg
Daniel R
DR
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. dgoldber@rdg.boehringer-ingelheim.com
Butz
Tanja
T
Cardozo
Mario G
MG
Eckner
Robert J
RJ
Hammach
Abdelhakim
A
Huang
Jessica
J
Jakes
Scott
S
Kapadia
Suresh
S
Kashem
Mohammed
M
Lukas
Susan
S
Morwick
Tina M
TM
Panzenbeck
Maret
M
Patel
Usha
U
Pav
Susan
S
Peet
Gregory W
GW
Peterson
Jeffrey D
JD
Prokopowicz
Anthony S
AS
Snow
Roger J
RJ
Sellati
Rosemarie
R
Takahashi
Hidenori
H
Tan
Jonathan
J
Tschantz
Matt A
MA
Wang
Xiao-Jun
XJ
Wang
Yong
Y
Wolak
John
J
Xiong
Pla
P
Moss
Neil
N
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; 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; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007546:Isoquinolines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)