Design and Synthesis of Orally Bioavailable Benzimidazoles as Raf Kinase Inhibitors

• Published in: Journal of medicinal chemistry 2008-11, Vol.51 (22), p.7049-7052
• Main Authors: Ramurthy, Savithri, Subramanian, Sharadha, Aikawa, Mina, Amiri, Payman, Costales, Abran, Dove, Jeff, Fong, Susan, Jansen, Johanna M, Levine, Barry, Ma, Sylvia, McBride, Christopher M, Michaelian, Jonah, Pick, Teresa, Poon, Daniel J, Girish, Sandhya, Shafer, Cynthia M, Stuart, Darrin, Sung, Leonard, Renhowe, Paul A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Benzimidazoles - administration & dosage; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Female; General aspects; Humans; Medical sciences; Mice; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary; raf Kinases - antagonists & inhibitors; raf Kinases - metabolism; Stereoisomerism; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801050k

A series of arylaminobenzimidazoles was designed and synthesized as Raf kinase inhibitors. Exploration of the structure−activity relationship resulted in compounds that are potent in vitro and show desirable in vivo properties.