Ao Wangwei, Ma Xueqin, Lin Youping, Wang Xiaojing, Song Wei, Wang Qinglin, Zhang Xiquan, Xu Hongjiang, Zhang Yinsheng
Jiangsu Key Laboratory of Targeted Antiviral Research, Chia Tai Tianqing Pharmaceutical Group Co., LTD, Nanjing, China.
J Labelled Comp Radiopharm. 2019 May 15;62(5):215-229. doi: 10.1002/jlcr.3715. Epub 2019 Apr 25.
A series of deuterated sofosbuvir analogs were designed and prepared with the aim of improving their pharmacokinetic properties. The devised synthetic routes allow for site-selective deuterium incorporation with high levels of isotopic purity. As expected, the deuterated analogs (37-44) are as efficacious as sofosbuvir when tested in vitro inhibition of viral replication (replicon) assays. Compared with sofosbuvir, deuterated analog 40 displays improved in vivo pharmacokinetics profiles in rats and dogs in terms of the metabolite and the prodrug. The Cmax and area under the curve (AUC) of 40 in dogs were increased by 3.4- and 2.7-fold, respectively. Due to the enhanced pharmacokinetic properties and the great synthetic advantage of an inexpensive deuterium source (D O) for 40, it was chosen for further investigation.
为改善其药代动力学性质，设计并制备了一系列氘代索磷布韦类似物。所设计的合成路线能够实现具有高同位素纯度的位点选择性氘掺入。正如预期的那样，在体外病毒复制（复制子）抑制试验中测试时，氘代类似物（37 - 44）与索磷布韦一样有效。与索磷布韦相比，氘代类似物40在大鼠和犬体内的代谢物和前药方面显示出改善的药代动力学特征。犬体内40的Cmax和曲线下面积（AUC）分别增加了3.4倍和2.7倍。由于其增强的药代动力学性质以及40使用廉价氘源（D₂O）的巨大合成优势，它被选择用于进一步研究。
