Bandarage Upul K, Clark Michael P, Perola Emanuele, Gao Huai, Jacobs Marc D, Tsai Alice, Gillespie Jeffery, Kennedy Joseph M, Maltais François, Ledeboer Mark W, Davies Ioana, Gu Wenxin, Byrn Randal A, Nti Addae Kwame, Bennett Hamilton, Leeman Joshua R, Jones Steven M, O'Brien Colleen, Memmott Christine, Bennani Youssef, Charifson Paul S
Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
ACS Med Chem Lett. 2017 Jan 18;8(2):261-265. doi: 10.1021/acsmedchemlett.6b00487. eCollection 2017 Feb 9.
JNJ-63623872 () 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 () 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.
JNJ-63623872（）是一种一流的口服生物可利用化合物，在治疗大流行性和季节性流感方面具有巨大潜力。我们在7-氮杂吲哚系列中的早期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这些7-氮杂吲哚类似物2位上观察到的醛氧化酶（AO）介导的代谢。在氮杂吲哚环的2位进行取代产生的类似物活性略低，但减少了AO介导的代谢。引入环氮生成了与母体2-H-7-氮杂吲哚等效的7-氮杂吲唑类似物，但令人惊讶的是，似乎并未改善AO介导的代谢。总体而言，我们鉴定出了多种具有增强AO稳定性的2-取代7-氮杂吲哚类似物，并展示了一种此类化合物（）的数据，该数据证明其在啮齿动物中具有良好的口服药代动力学特征。这些类似物有潜力作为抗流感药物进一步开发用于治疗流感。
