Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity.

ID: ALA4619714

Journal: Bioorg Med Chem Lett

Title: Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity.

Authors: Lv K, Li W, Wu S, Geng Y, Wang A, Yang L, Huang M, Chowdhury K, Li Y, Liu M.

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.

CiteXplore: 32173194

DOI: 10.1016/j.bmcl.2020.127103

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