In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses.
In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses.
复制标题
DOI：
10.1021/acs.jmedchem.7b01536
复制
发表时间：
2018-02-08
影响因子：
7.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang Y;Hu Y;Xu S;Zhang Y;Musharrafieh R;Hau RK;Ma C;Wang J
流感病毒是呼吸道病原体，既是季节性流感流行的原因，也是偶尔发生的流感大流行的原因。奥司他韦治疗窗口狭窄，加上出现耐药性，需要下一代抗病毒药物。随着我们对开发AM2-S31N抑制剂作为口服抗流感病毒药物的持续兴趣，我们报告了AM2-S31N抑制剂体外药代动力学(PK)性质的优化进展。一些AM2-S31N抑制剂，包括化合物10b，被发现具有有效的通道阻断，单一到亚微摩尔的抗病毒活性，以及良好的体外PK特性。化合物10b的抗病毒作用与羧酸奥司他韦有协同作用。有趣的是，结合动力学研究(Kd、Kon和Koff)揭示了几种AM2-S31N抑制剂具有相似的Kd值但Kon和Koff值显著不同。总体而言，这项研究确定了一种有效的先导化合物(10b)，具有改进的体外PK特性，适合于体内小鼠模型研究。
Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound 10b, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties. The antiviral efficacy of compound 10b was also synergistic with oseltamivir carboxylate. Interestingly, binding kinetic studies (Kd, Kon and Koff) revealed several AM2-S31N inhibitors that have similar Kd values but significantly different Kon and Koff values. Overall, this study identified a potent lead compound (10b) with improved in vitro PK properties that is suitable for the in vivo mouse model studies.
登录
查看更多内容
影响因子：
4.9
作者：
Meletiadis, Joseph;Pournaras, Spyros;Walsh, Thomas J.
通讯作者：
Walsh, Thomas J.
影响因子：
9.4
作者：
Hatakeyama, S;Sakai-Tagawa, Y;Kawaoka, Y
通讯作者：
Kawaoka, Y
影响因子：
62.1
作者：
Wanka, Lukas;Iqbal, Khalid;Schreiner, Peter R.
通讯作者：
Schreiner, Peter R.
影响因子：
4.8
作者：
Matsuzaki Y;Mizuta K;Aoki Y;Suto A;Abiko C;Sanjoh K;Sugawara K;Takashita E;Itagaki T;Katsushima Y;Ujike M;Obuchi M;Odagiri T;Tashiro M
通讯作者：
Tashiro M
影响因子：
5.9
作者：
Hurt, Aeron C.
通讯作者：
Hurt, Aeron C.