Discovery, optimization and biological evaluation of novel HBsAg production inhibitors.

Hepatitis B virus (HBV) infection is a major global health problem. HBsAg inhibitors are expected to reduce the production of HBsAg via inhibiting host proteins PAPD5 & PAPD7 and finally achieve the ideal goal of "functional cure". In this work, a series of tetrahydropyridine (THP) derivatives with a bridged ring were synthesized and evaluated for their inhibiting HBsAg production and HBV DNA activity. Among them, compound 17i was identified as potent HBsAg production inhibitor with excellent in vitro anti-HBV potency (HBV DNA EC50 = 0.018 µM, HBsAg EC50 = 0.044 µM) and low toxicity (CC50 > 100 µM). Moreover, 17i exhibited favorable in vitro/in vivo DMPK properties in mice. 17i could also significantly reduce serum HBsAg and HBV DNA levels (1.08 and 1.04 log units, respectively) in HBV transgenic mice.

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

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 (D2 O) for 40, it was chosen for further investigation.

Synthesis of deuterium-labeled crizotinib, a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).

To more accurately and rapidly achieve quantitative detection of clinical crizotinib samples, stable isotope labeled crizotinib was required as an internal standard. We have developed a method to prepare racemic [D9 ] crizotinib using a base-catalyzed H/D exchange of both nitroso compound 2 and the acetophenone compound 6 with D2 O and NaBD4 reduction of 7 as the key steps to introduce the 9 deuterium atoms. Starting with 4-hydroxypiperidine, 14-step synthesis furnished the desired racemic [D9 ] crizotinib 18. The deuterium-labeled compound 18 with the chemical purity of 99.62% was applicable for use as internal standards in the drug clinical study.