Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2

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• 作者：Michael P. Clark ; Mark W. Ledeboer ; Ioana Davies ; Randal A. Byrn ; Steven M. Jones ; Emanuele Perola ; Alice Tsai ; Marc Jacobs ; Kwame Nti-Addae ; Upul K. Bandarage ; Michael J. Boyd ; Randy S. Bethiel ; John J. Court ; Hongbo Deng ; John P. Duffy ; Warren A. Dorsch ; Luc J. Farmer ; Huai Gao ; Wenxin Gu ; Katrina Jackson ; Dylan H. Jacobs ; Joseph M. Kennedy ; Brian Ledford ; Jianglin Liang ; Fran莽ois Maltais ; Mark Murcko ; Tiansheng Wang ; M. Woods Wannamaker ; Hamilton B. Bennett ; Joshua R. Leeman ; Colleen McNeil ; William P. Taylor ; Christine Memmott ; Min Jiang ; Rene Rijnbrand ; Christopher Bral ; Ursula Germann ; Azin Nezami ; Yuegang Zhang ; Francesco G. Salituro ; Youssef L. Bennani ; Paul S. Charifson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6668-6678
• 全文大小：580K
• ISSN：1520-4804

文摘

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A.Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105鈭?14) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.