RG7834：一類具有新作用機制的選擇性口服小分子HBV抑製劑

導讀

近日科學家報道了二氫喹諾酮（DHQ）衍生物的抗HBV活性以及構效關係，其中化合物RG7834是一種具有高度選擇性和口服生物活性的乙肝病毒抑製劑，它能抑制病毒抗原和病毒的DNA活性，而且具有新的作用機制。相關研究發表於J. Med. Chem.，題為「Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action」。

結果速覽

科學家合成了一系列DHQ衍生物，研究了它們的構效關係，它們的靶點是PAPD5 和PAPD7。具有代表性的先導化合物RG7834對乙型肝炎病毒感染肝細胞中的HBsAg、HBeAg和HBV-DNA有較強的抑制作用(IC50為低nM水平)，但未見細胞毒性（50 μM時）。此外，RG7834對HBV具有很強的特異性，對15種其他的病毒沒有抑制作用。在老鼠和猴子體內進行試驗，結果表明該化合物在臨床前期毒理學研究中具有良好的耐受性。此外，RG7834在人肝嵌合uPA-SCID小鼠模型中顯示出前所未有的PD效應。所有數據都支持RG7834進一步的臨床研究。以ETV（恩替卡韋）為對照，研究了HBV感染的人肝嵌合uPA-SCID小鼠體內抗HBV效果。用4mg/kg每日兩次給葯21天，RG7834顯著降低了兩種抗原的含量，而ETV的降低效果不明顯(如下圖)。

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.

本期編輯：碳硼酸

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