The discovery of potent and selective 4-aminothienopyridines as B-Raf kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 1; pp. 66 - 70
• Main Authors: Tang, Jun, Lackey, Karen E., Dickerson, Scott H.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2013; Elsevier
• Subjects: Aminopyridines - chemical synthesis; Aminopyridines - chemistry; Aminopyridines - metabolism; B-Raf inhibitor; bioassays; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Drug Evaluation, Preclinical; enzyme inhibitors; Knowledge-based design; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - metabolism; phosphotransferases (kinases); Physical Sciences; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; pyridines; Science & Technology; Structure-Activity Relationship; Thienopyridines - chemical synthesis; Thienopyridines - chemistry; Thienopyridines - metabolism; Knowledge-based design; B-Raf inhibitor; DESIGN
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.020

A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50=5.1, 16.6nM) and cellular assay (IC50=0.2, 0.2μM), but also had an outstanding selectivity profile against other kinases. A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50=5.1, 16.6nM) and cellular assay (IC50=0.2, 0.2μM), but also had an outstanding selectivity profile against other kinases.