Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza

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• 作者：Upul K. BandarageMichael P. Clark ; Emanuele PerolaHuai Gao ; Marc D. Jacobs ; Alice Tsai ; Jeffery Gillespie ; Joseph M. Kennedy ; François Maltais ; Mark W. Ledeboer ; Ioana Davies ; Wenxin Gu ; Randal A. Byrn ; Kwame Nti Addae ; Hamilton Bennett ; Joshua R. Leeman ; Steven M. Jones ; Colleen O’Brien ; Christine Memmott ; Youssef 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：261-265
• 全文大小：331K
• ISSN：1948-5875

文摘

JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.