导 读
近日科学家报道了二氢喹诺酮（DHQ）衍生物的抗HBV活性以及构效关系，其中化合物RG7834是一种具有高度选择性和口服生物活性的乙肝病毒抑制剂，它能抑制病毒抗原和病毒的DNA活性，而且具有新的作用机制。相关研究发表于J. Med. Chem.，题为“Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action”。
结果速览
科学家合成了一系列DHQ衍生物，研究了它们的构效关系，它们的靶点是PAPD5 和PAPD7。具有代表性的先导化合物RG7834对乙型肝炎病毒感染肝细胞中的HBsAg、HBeAg和HBV-DNA有较强的抑制作用(IC50为低nM水平)，但未见细胞毒性（50 M时）。此外，RG7834对HBV具有很强的特异性，对15种其他的病毒没有抑制作用。在老鼠和猴子体内进行试验，结果表明该化合物在临床前期毒理学研究中具有良好的耐受性。此外，RG7834在人肝嵌合uPA-SCID小鼠模型中显示出前所未有的PD效应。所有数据都支持RG7834进一步的临床研究。以ETV（恩替卡韦）为对照，研究了HBV感染的人肝嵌合uPA-SCID小鼠体内抗HBV效果。用4mg/kg每日两次给药21天，RG7834显著降低了两种抗原的含量，而ETV的降低效果不明显(如下图)。
ABSTRACT: Chronic hepatitis B virus (HBV) infection is a serious public health burden and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.
本期编辑：碳硼酸