Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, PR China; School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, PR China.
Eur J Med Chem. 2020 Aug 15;200:112423. doi: 10.1016/j.ejmech.2020.112423. Epub 2020 May 12.
The most of potent neuraminidase inhibitors as zwitterions with poor lipophilicity suffered from the poor oral bioavailability. Herein, we describe a rational journey to discover a non-zwitterionic neuraminidase inhibitor 24a containing urea. It showed potent inhibitions against neuraminidases from group 1(H5N1 and H1N1) and group 2 (H3N2) subtypes and exhibited more strong inhibitory activities against neuraminidases from H274Y mutants than oseltamivir carboxylate. Whether administrated by orally or intravenous injection, the pharmacokinetic profile of compound 24a in SD rats were improved compared to oseltamivir carboxylate.
大多数作为两性离子的强效神经氨酸酶抑制剂由于亲脂性差而口服生物利用度差。在此，我们描述了一条合理的发现之旅，以发现一种非两性离子神经氨酸酶抑制剂 24a，其中含有脲。它对来自 1 组（H5N1 和 H1N1）和 2 组（H3N2）亚型的神经氨酸酶表现出强烈的抑制作用，并且对 H274Y 突变体的神经氨酸酶的抑制活性比奥司他韦羧酸盐更强。在 SD 大鼠中，无论通过口服还是静脉注射给予，化合物 24a 的药代动力学特征均优于奥司他韦羧酸盐。
