Development of Fluorinated Sulfamoylbenzamide Derivatives as Antiviral Agents aga

描述（由申请方提供）：这是一项I期提案，旨在确定开发新发现的氟化氨磺酰苯甲酰胺（FSBA）衍生物作为治疗慢性B型肝炎病毒（HBV）感染的治疗药物的可行性。这些分子已被鉴定为HBV前基因组（pg）RNA糖苷化的抑制剂，其对于随后的病毒DNA合成是必需的。与目前FDA批准的抑制HBV DNA聚合酶的抗病毒核苷（酸）类似物的机制不同，pgRNA组装成核衣壳代表了一种新的治疗靶点，因此FSBA化合物应补充目前的抗病毒药物。通过广泛的构效关系（SAR）研究，我们现在已经获得了具有纳摩尔级抗病毒活性的FSBA化合物。在这个I期项目中，我们建议推进具有最有利的ADME、安全性和药代动力学（PK）特征的FSBA先导化合物，用于在HBV转基因小鼠模型中进行体内抗病毒疗效研究。在转基因小鼠模型中证实了体内抗病毒功效后，我们将在II期研究中进一步评估先导FSBAs在HBV感染的人嵌合uPA-SCID小鼠模型中的安全性特征和抗病毒功效。在第二阶段结束时，我们将推进一个主要候选人进行广泛的IND使能研究，并准备一个人体临床试验病例。

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.