Discovery and in Vivo Evaluation of Dual PI3K尾/未 Inhibitors

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• 作者：Felix Gonzalez-Lopez de Turiso ; Youngsook Shin ; Matthew Brown ; Mario Cardozo ; Yi Chen ; David Fong ; Xiaolin Hao ; Xiao He ; Kirk Henne ; Yi-Ling Hu ; Michael G. Johnson ; Todd Kohn ; Julia Lohman ; Helen J. McBride ; Lawrence R. McGee ; Julio C. Medina ; Daniela Metz ; Kent Miner ; Deanna Mohn ; Vatee Pattaropong ; Jennifer Seganish ; Jillian L. Simard ; Sharon Wannberg ; Douglas A. Whittington ; Gang Yu ; Timothy D. Cushing
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7667-7685
• 全文大小：909K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3K尾/未 dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3K尾 and 未 isoforms in the treatment of a number of inflammatory diseases.