Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2

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• 作者：Luc J. Farmer ; Michael P. ClarkMichael J. Boyd ; Emanuele PerolaSteven M. Jones ; Alice Tsai ; Marc D. Jacobs ; Upul K. Bandarage ; Mark W. Ledeboer ; Tiansheng WangHongbo Deng ; Brian Ledford ; Wenxin Gu ; John P. Duffy ; Randy S. Bethiel ; Dean Shannon ; Randal A. Byrn ; Joshua R. Leeman ; Rene Rijnbrand ; Hamilton B. Bennett ; Colleen O’Brien ; Christine Memmott ; Kwame Nti-Addae ; Youssef L. Bennani ; Paul S. Charifson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：8
• 期：2
• 页码：256-260
• 全文大小：396K
• ISSN：1948-5875

文摘

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.