Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-03-09 , DOI: 10.1016/j.bmcl.2020.127103 Kai Lv , Wenyan Li , Shuo Wu , Yunhe Geng , Apeng Wang , Lu Yang , Menghao Huang , Kushan Chowdhury , Yuhuan Li , Mingliang Liu
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.
中文翻译:
NVR3-778的氨基酸前药:设计,合成和抗HBV活性
NVR3-778的一系列氨基酸前药是目前正在接受II期临床试验的有效抗HBV候选药物,已被设计并合成为新的抗HBV药物。除了1E,他们都显示大致相当于抗HBV活性(IC 50,0.28-0.56μM)至NVR3-778(IC 50,0.26μM)。发现化合物1a是NVR3-778的L-缬氨酸酯前药,与我们预期的相比,其水溶性(0.7 mg / mL,pH 2)显着改善,并且细胞毒性(CC 50 > 10 µM)比NVR3-778( CC 50,4.81μM)。此外,1a还表现出可接受的PK特性,并且在体内具有可比性 HBV DNA流体动力学小鼠模型的功效优于NVR3-778,表明它可以作为进一步抗HBV药物发现的有前途的先导化合物。