Discovery of pyrimidine benzimidazoles as Lck inhibitors: part I.
A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src kinase family. Highly efficient parallel syntheses were devised to prepare analogues for SAR studies. A number of these 4-amino-6-benzimidazole-pyrimidines exhibited single-digit nanomolar IC(50)s against Lck in biochemical and cellular assays. These 4-amino-6-benzimidazole-pyrimidines represent a new class of tyrosine kinase inhibitors.
Zhang
Guobao
G
Genomics Institute of the Novartis Research Foundation (GNF), Medicinal Chemistry, 10715 John Jay Hopkins Drive, San Diego, CA 92121, USA. gzhang@gnf.org
Ren
Pingda
P
Gray
Nathanael S
NS
Sim
Taebo
T
Liu
Yi
Y
Wang
Xia
X
Che
Jianwei
J
Tian
Shin-Shay
SS
Sandberg
Mark L
ML
Spalding
Tracy A
TA
Romeo
Russell
R
Iskandar
Maya
M
Chow
Donald
D
Martin Seidel
H
H
Karanewsky
Donald S
DS
He
Yun
Y
D001327:Autoimmune Diseases / Q000188:drug therapy; D001562:Benzimidazoles / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D008968:Molecular Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000378:metabolism
D001562:Benzimidazoles; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; C030986:pyrimidine