Development of Fluorinated Sulfamoylbenzamide Derivatives as Antiviral Agents aga

描述(由申请人提供)：这是一项第一阶段的提案，旨在确定开发新发现的氟磺酰基苯甲酰胺(FSBA)衍生物作为治疗慢性乙肝病毒(乙肝)感染的治疗剂的可行性。这些分子已被确定为乙肝病毒前基因组(PG)RNA包裹的抑制剂，这是后续病毒DNA合成所必需的。与目前FDA批准的抑制HBVDNA聚合酶的抗病毒核(T)类似物的机制不同，pgRNA组装到核衣壳中代表着一个新的治疗靶点，因此FSBA化合物应该是当前抗病毒药物的补充。通过广泛的结构-活性-关系(SAR)研究，我们现在已经获得了具有纳米分子抗病毒活性的FSBA化合物。在这个第一阶段的项目中，我们建议开发具有最有利的ADME、安全性和药代动力学(PK)特征的先导FSBA化合物，用于体内抗病毒转基因小鼠模型的抗病毒效果研究。在确认了转基因小鼠模型的体内抗病毒效果后，我们将在第二阶段研究中进一步评估先导FSBAs在乙肝病毒感染的人uPA-SCID嵌合小鼠模型中的安全性和抗病毒效果。在第二阶段结束时，我们将推进一名主要候选者进行广泛的IND使能研究，并为人类临床试验准备一个案例。

DESCRIPTION (provided by applicant): This is a phase I proposal to determine the feasibility of developing newly discovered fluorinated sulfamoylbenzamide (FSBA) derivatives as therapeutic agents for the treatment of chronic hepatitis B virus (HBV) infection. These molecules have been identified as inhibitors of HBV pregenomic (pg) RNA encapsidation, which is essential for the subsequent viral DNA synthesis. Distinct from the mechanism of the currently FDA-approved antiviral nucleos(t)ide analogues that inhibit HBV DNA polymerase, pgRNA assembly into nucleocapsid represents a novel therapeutic target and the FSBA compounds should thus complement the current antiviral medications. Through an extensive structure-activity-relationship (SAR) study, we have now obtained FSBA compounds with nanomolar antiviral activity. In this Phase I project, we propose to advance lead FSBA compounds with the most favorable ADME, safety and pharmacokinetics (PK) profiles for antiviral efficacy study in the HBV transgenic mouse model in vivo. Having confirmed the in vivo antiviral efficacy in the transgenic mice model, we will further evaluate the safety profile and antiviral efficacy of the lead FSBAs in HBV infected human chimeric uPA-SCID mice model in Phase II study. At the end of Phase II, we will advance one lead candidate for extensive IND enabling studies, and prepare a case for human clinical trial.