Journal of labelled compounds and radiopharmaceuticals p. 215 - 229 (2019)
Update date:2022-08-04
Topics:
Ao, Wangwei
Ma, Xueqin
Lin, Youping
Wang, Xiaojing
Song, Wei
Wang, Qinglin
Zhang, Xiquan
Xu, Hongjiang
Zhang, Yinsheng
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 (D2O) for 40, it was chosen for further investigation.
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