Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity. Issue 9 (1st May 2020)

• Record Type: Journal Article
• Authors: Lv, Kai; Li, Wenyan; Wu, Shuo; Geng, Yunhe; Wang, Apeng; Yang, Lu; Huang, Menghao; Chowdhury, Kushan; Li, Yuhuan; Liu, Mingliang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 9(2020)
• Publication Date: 2020-05-01
• Subjects: NVR3-778 -- Anti-HBV -- Prodrug -- Capsid assembly modulators; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127103
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Most of the new targets displayed roughly comparable anti-HBV activity to NVR3-778. Prodrug 1a showed significantly improved water solubility. Prodrug 1a exhibited lower cytotoxicity than NVR3-778. Prodrug 1a exhibited acceptable PK properties and in vivo anti-TB efficacy. Abstract: A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28–0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l - valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.