Discovery and initial SAR of imidazoquinoxalines as inhibitors of the Src-family kinase p56(Lck).
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.
Chen
Ping
P
Department of Discovery Chemistry, Bristol Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. ping.chen@bms.com
Norris
Derek
D
Iwanowicz
Edwin J
EJ
Spergel
Steven H
SH
Lin
James
J
Gu
Henry H
HH
Shen
Zhongqi
Z
Wityak
John
J
Lin
Tai-An
TA
Pang
Suhong
S
De Fex
Henry F
HF
Pitt
Sidney
S
Shen
Ding Ren
DR
Doweyko
Arthur M
AM
Bassolino
Donna A
DA
Roberge
Jacques Y
JY
Poss
Michael A
MA
Chen
Bang-Chi
BC
Schieven
Gary L
GL
Barrish
Joel C
JC
D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011810:Quinoxalines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases