J Med Chem. 2018 Dec 13;61(23):10619-10634. doi: 10.1021/acs.jmedchem.8b01245. Epub 2018 Oct 17.
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.
慢性乙型肝炎病毒 (HBV) 感染是一个严重的公共卫生负担，目前的治疗方法无法达到令人满意的治愈率。目前，人们对新型治疗药物有着高度未满足的医疗需求，这些药物的作用机制 (MOA) 与现有标准治疗方法有所不同。RG7834 是一种来自二氢喹啉酮 (DHQ) 化学系列的化合物，是一种具有全新作用机制的首创的高度选择性、可口服生物利用的 HBV 抑制剂，可降低病毒抗原和病毒 DNA。本文报道了从表型筛选中发现 RG7834 以及 DHQ 化学系列的构效关系 (SAR)。RG7834 可以在病毒筛选中选择性抑制 HBV，但不抑制其他 DNA 或 RNA 病毒。本文描述了 RG7834 的体外和体内特性，数据支持进一步开发这种化合物作为慢性 HBV 治疗药物。
