Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 160 00 Prague 6, Czech Republic.
Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic.
J Med Chem. 2021 Nov 25;64(22):16425-16449. doi: 10.1021/acs.jmedchem.1c01444. Epub 2021 Oct 29.
This study describes the discovery of novel prodrugs bearing tyrosine derivatives instead of the phenol moiety present in FDA-approved tenofovir alafenamide fumarate (TAF). The synthesis was optimized to afford diastereomeric mixtures of novel prodrugs in one pot (yields up to 86%), and the epimers were resolved using a chiral HPLC column into fast-eluting and slow-eluting epimers. In human lymphocytes, the most efficient tyrosine-based prodrug reached a single-digit picomolar EC value against HIV-1 and nearly 300-fold higher selectivity index (SI) compared to TAF. In human hepatocytes, the most efficient prodrugs exhibited subnanomolar EC values for HBV and up to 26-fold higher SI compared to TAF. Metabolic studies demonstrated markedly higher cellular uptake of the prodrugs and substantially higher levels of released tenofovir inside the cells compared to TAF. These promising results provide a strong foundation for further evaluation of the reported prodrugs and their potential utility in the development of highly potent antivirals.
本研究描述了新型前药的发现，这些前药带有酪氨酸衍生物，而不是已获 FDA 批准的替诺福韦艾拉酚胺富马酸盐（TAF）中的酚部分。合成经过优化，一锅法提供了新型前药的非对映异构体混合物（产率高达 86%），并使用手性 HPLC 柱将差向异构体拆分成为快速洗脱和缓慢洗脱的差向异构体。在人淋巴细胞中，最有效的酪氨酸基前药对 HIV-1 的 EC 值达到了个位数皮摩尔，与 TAF 相比，选择性指数（SI）高近 300 倍。在人肝细胞中，最有效的前药对 HBV 的 EC 值达到了亚纳摩尔，与 TAF 相比，SI 高 26 倍。代谢研究表明，与 TAF 相比，前药的细胞摄取率明显更高，细胞内释放的替诺福韦水平也显著更高。这些有前景的结果为进一步评估所报道的前药及其在开发高效抗病毒药物方面的潜在用途提供了坚实的基础。
