Molecular design, synthesis, and structure-Activity relationships leading to the potent and selective p56(lck) inhibitor BMS-243117.
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 microM) against T-cell proliferation.
Das
Jagabandhu
J
Bristol-Myers Squibb Pharmaceutical Research Institute, 08543-4000, Princeton, NJ, USA. jagabandhu.das@bms.com
Lin
James
J
Moquin
Robert V
RV
Shen
Zhongqi
Z
Spergel
Steven H
SH
Wityak
John
J
Doweyko
Arthur M
AM
DeFex
Henry F
HF
Fang
Qiong
Q
Pang
Suhong
S
Pitt
Sidney
S
Shen
Ding Ren
DR
Schieven
Gary L
GL
Barrish
Joel C
JC
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry
C481959:BMS-243117; D004791:Enzyme Inhibitors; D013844:Thiazoles; D000255:Adenosine Triphosphate; D014508:Urea; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)