State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China.
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China.
J Med Chem. 2020 Aug 13;63(15):8134-8145. doi: 10.1021/acs.jmedchem.0c00346. Epub 2020 Jul 21.
HBV capsid assembly has been viewed as an attractive target for new antiviral therapies against HBV. On the basis of a lead compound , we further investigated this target to identify novel active compounds with appropriate anti-HBV potencies and improved pharmacokinetic (PK) properties. Structure-activity relationship studies based on metabolic pathways of led to the identification of a phthalazinone derivative with appropriate anti-HBV potencies (IC = 0.014 ± 0.004 μM ), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of resulted in a 2.67 log reduction of the HBV DNA viral load during a 4-week treatment with 150 mg/kg dosing twice daily.
HBV 衣壳组装一直被视为针对 HBV 的新型抗病毒治疗的有吸引力的靶标。在先导化合物的基础上，我们进一步研究了这一靶点，以鉴定具有适当抗 HBV 效力和改善药代动力学 (PK) 特性的新型活性化合物。基于 lead compound 的代谢途径的结构-活性关系研究导致了鉴定出具有适当抗 HBV 效力（IC = 0.014 ± 0.004 μM）的邻苯二甲酰亚胺衍生物 ，其具有高口服生物利用度和肝脏暴露。在 AAV-HBV/小鼠模型中，在 150 mg/kg 剂量每天两次给药 4 周的治疗过程中， administration of 导致 HBV DNA 病毒载量降低 2.67 个对数。
