title: Discovery of pyrimidine benzimidazoles as Lck inhibitors: part I.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), Medicinal Chemistry, 10715 John Jay Hopkins Drive, San Diego, CA 92121, USA. gzhang@gnf.org
authors.forename: Guobao
authors.initials: G
authors.lastname: Zhang
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Che
authors.forename: Shin-Shay
authors.initials: SS
authors.lastname: Tian
authors.forename: Mark L
authors.initials: ML
authors.lastname: Sandberg
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Spalding
authors.forename: Russell
authors.initials: R
authors.lastname: Romeo
authors.forename: Maya
authors.initials: M
authors.lastname: Iskandar
authors.forename: Donald
authors.initials: D
authors.lastname: Chow
authors.forename: H
authors.initials: H
authors.lastname: Martin Seidel
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: Yun
authors.initials: Y
authors.lastname: He
mesh_terms: 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
chemical_list: D001562:Benzimidazoles; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; C030986:pyrimidine