Development of Sulfamoylbenzamide Derivatives as Antiviral Agents against HBV Inf

描述(申请人提供)：这是一项开发新发现的氨基苯甲酰胺衍生物作为治疗慢性乙肝病毒(乙肝病毒)感染的治疗药物的建议。这些分子已被确定为乙肝病毒前基因组(PG)RNA包埋的抑制因子，这是乙肝病毒生命周期中的关键步骤。PgRNA是HBVDNA逆转录复制的模板，它与病毒DNA聚合酶一起被包裹到核衣壳中，对随后的病毒DNA合成是必不可少的。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了一个新的治疗靶点，应该是对当前抗病毒药物的补充。通过对591个磺酰苯甲酰胺类化合物的构效关系研究，我们已经得到了具有亚微摩尔抗病毒活性的化合物，其中DVR-23的抗病毒活性最好(EC50=280 nM，EC90=860 nM)。在这个第一阶段的项目中，我们建议进一步优化当前化合物的磺胺部分，以确定具有优越的抗病毒、药代动力学和毒理学特征的先导化合物，并在体内的乙肝病毒转基因小鼠模型中测试它们的抗病毒效果。 与公共卫生相关：这是一项建议，将新发现的乙肝病毒(乙肝)抑制剂，称为磺酰苯甲酰胺衍生物，开发成治疗慢性乙肝的药物。这些化合物的功能是通过干扰病毒DNA合成模板的包装，即前基因组RNA，构成一种与目前FDA批准的抗乙肝药物不同的机制。因此，该药物可以单独使用，也可以与现有药物联合使用，以达到延长临床疗效的目的。

DESCRIPTION (provided by applicant): This is a proposal to develop newly discovered sulfamoylbenzamide 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, a critical step in the life cycle of HBV. PgRNA is the template for reverse transcriptional replication of HBV DNA, and its encapsidation into nucleocapsid with viral DNA polymerase 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 nucleocapsids represents a novel therapeutic target and should complement the current antiviral medications. Through an extensive structure-activity-relationship (SAR) study of 591 sulfamoylbenzamide derivatives, we have already obtained compounds with sub-micromolar antiviral activity, with the best being DVR-23 (EC50 = 280 nM, EC90 = 860nM). In this Phase I project, we propose to further optimize the sulfonamide moiety of the current compounds to identify leads with superior antiviral, pharmacokinetic and toxicology profiles, and to test their antiviral efficacy in the HBV transgenic mouse model in vivo PUBLIC HEALTH RELEVANCE: This is a proposal to develop newly discovered inhibitors of hepatitis B virus (HBV), referred to as sulfamoylbenzamide derivatives, into a drug for treatment of chronic hepatitis B. These compounds function by interfering with packaging of the template for viral DNA synthesis, pregenomic RNA, constituting a mechanism which is distinct from the currently FDA-approved anti-HBV medications. Hence, the drug may be of use by itself or in combination with current medications to achieve extended clinical benefits.