Synthesis and biological evaluation of deuterated sofosbuvir analogs as HCV NS5B inhibitors with enhanced pharmacokinetic properties

摘要

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 2 O) for 40 , it was chosen for further investigation.