Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza
Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza
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DOI：
10.1021/acsmedchemlett.6b00487
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发表时间：
2017-02-01
影响因子：
4.2
通讯作者：
Charifson, Paul S.
中科院分区：
文献类型：
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作者：
Bandarage, Upul K.;Clarke, Michael P.;Charifson, Paul S.
JNJ-63623872（2）是一种一流的口服生物利用度化合物，具有治疗大流行性和季节性流感的巨大潜力。在我们的7-氮杂吲哚系列中，早期的先导优化工作集中在嘧啶-7-氮杂吲哚基序上的1，3-二氨基环己基酰胺和脲取代：在这项工作中，我们探索了两种策略来消除在这些7-氮杂吲哚类似物的2位观察到的醛氧化酶（AO）介导的代谢。在氮杂吲哚环的2-位的取代产生稍微不太有效的类似物，但减少AO介导的代谢。掺入环氮产生7-氮杂吲唑类似物，其与母体2-H-7氮杂吲哚等效，但令人惊讶的是，似乎没有改善AO介导的代谢。总之，我们鉴定了具有增强的AO稳定性的多种2-取代的7-氮杂吲哚类似物，并且我们提供了一种这样的化合物（12）的数据，其在啮齿动物中表现出有利的口服药代动力学特征。这些类似物具有进一步开发为用于治疗流感的抗流感剂的潜力。
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-7azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7azaindole 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.