Design, synthesis and anti-HBV activity of NVR3-778 derivatives

Kai Lv; Shuo Wu; Wenyan Li; Yunhe Geng; Meng Wu; Jinming Zhou; Yuhuan Li; Qiang Gao; Mingliang Liu

doi:10.1016/j.bioorg.2019.103363

Design, synthesis and anti-HBV activity of NVR3-778 derivatives

Bioorg Chem. 2020 Jan:94:103363. doi: 10.1016/j.bioorg.2019.103363. Epub 2019 Oct 14.

Authors

Kai Lv¹, Shuo Wu¹, Wenyan Li², Yunhe Geng³, Meng Wu¹, Jinming Zhou⁴, Yuhuan Li⁵, Qiang Gao¹, Mingliang Liu⁶

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
² College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, China.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, China.
⁴ Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua 321004, China.
⁵ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: yuhuanlibj@126.com.
⁶ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: lmllyx@126.com.

PMID: 31669092
DOI: 10.1016/j.bioorg.2019.103363

Abstract

NVR3-778, one of the most advanced capsid assembly modulators (CAMs), is currently in phase II clinical trial for the treatment of HBV infection. In this study, we reported the first structure optimization of NVR3-778. Compound 2d was found to exhibit more potent anti-HBV activity (IC₅₀: 0.25 µM), lower cytotoxicity (CC₅₀: 10.68 µM) and higher selectivity index (SI: 40.72) than NVR3-778 (IC₅₀: 0.33 µM; CC₅₀: 5.14 µM; SI: 18.36) in vitro, and also display similar inhibitory effect on the assembly of HBV capsids as NVR3-778. Molecular docking further suggested that compound 2d might form a stronger interaction with core protein. Moreover, compound 2d also showed acceptable pharmacokinetic profiles. Currently compound 2d was selected as a new lead for further modifications, and studies to determine the in vivo anti-HBV studies of 2d will begin soon.

Keywords: Anti-HBV activity; Capsid assembly modulators; NVR3-778; Structure modification; Sulfamoylbenzamides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Design*
Hepatitis B virus / drug effects*
Humans
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Structure-Activity Relationship

Substances

Antiviral Agents
Benzamides
NVR 3-778
Piperidines