Discovery of pyrimidine benzimidazoles as Lck inhibitors: Part I

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 20; pp. 5618 - 5621
• Main Authors: Zhang, Guobao, Ren, Pingda, Gray, Nathanael S., Sim, Taebo, Liu, Yi, Wang, Xia, Che, Jianwei, Tian, Shin-Shay, Sandberg, Mark L., Spalding, Tracy A., Romeo, Russell, Iskandar, Maya, Chow, Donald, Martin Seidel, H., Karanewsky, Donald S., He, Yun
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.10.2008; Elsevier
• Subjects: Autoimmune disease; Autoimmune Diseases - drug therapy; Benzimidazoles - antagonists & inhibitors; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Drug Design; Humans; Immunomodulators; Inhibitory Concentration 50; Kinase inhibitor; Lck inhibitor; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - antagonists & inhibitors; Medical sciences; Models, Chemical; Molecular Conformation; Pharmacology. Drug treatments; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidine benzimidazoles; Pyrimidines - antagonists & inhibitors; Pyrimidines - chemistry; Solubility; src-Family Kinases - metabolism; Structure-Activity Relationship; Transplantation rejection; Pyrimidine benzimidazoles; Autoimmune disease; Transplantation rejection; Lck inhibitor; Kinase inhibitor; Nitrogen heterocycle; Selectivity; Morpholine derivatives; Modeling; Pyridine derivatives; Signal transduction; Structure activity relation; Chlorine Organic compounds; Six membered ring; Molecular model; Bicyclic compound; Aromatic compound; Chemical synthesis; Aminoalcohol; Enzyme; Transferases; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Immunomodulator; Benzimidazole derivatives; Pyrimidine derivatives; Piperazine derivatives
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.08.104

A series of 4-amino-6-benzimidazole-pyrimidines were designed and synthesized as potent Lck inhibitors. 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 50s against Lck in biochemical and cellular assays. These 4-amino-6-benzimidazole-pyrimidines represent a new class of tyrosine kinase inhibitors.