Development of Sulfamoylbenzamide Derivatives as Antiviral Agents against HBV Inf

磺胺酰苯甲酰胺衍生物作为抗 HBV Inf 抗病毒药物的开发

• 批准号: 8394119
• 负责人: Ju-Tao Guo
• 金额: $ 30万
• 依托单位: ENANTIGEN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394119
• 关键词: Animal Model; Antiviral Agents; Back; Binding; Biological Availability; Capsid; Chemicals; Chronic Hepatitis B; Clinical; Clinical Trials; Combined Modality Therapy; Complement; DNA biosynthesis; DNA-Directed DNA Polymerase; Data; Development; Dose; Drug Kinetics; Drug resistance; Duck Hepatitis B Virus; Excretory function; FDA approved; Frequencies; Genome; Goals; Hepatitis B Virus; Hepatocyte; Human; In Vitro; Kinetics; Lead; Life Cycle Stages; Metabolism; Modeling; Modification; Molecular Target; Nucleocapsid; Pharmaceutical Preparations; Phase; Polymerase; Property; Proteins; RNA; SCID Mice; Series; Structure-Activity Relationship; Sulfonamides; Testing; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Toxicity Tests; Toxicology; Transgenic Mice; Treatment Protocols; Viral; Virus Replication; Woodchuck Hepatitis B Virus; Work; absorption; analog; anti-hepatitis B; cytotoxicity; design; drug resistant virus; hepatitis B virus P protein; high throughput screening; improved; in vivo; inhibitor/antagonist; mouse model; new therapeutic target; novel; pgRNA; phase 1 study; phase 2 study; pre-clinical; protein folding; stable cell line; viral DNA

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.

描述（由申请人提供）：这是一个开发新发现的磺胺酰苄胺衍生物作为治疗慢性乙型肝炎病毒（HBV）感染的药物的提案。这些分子已被确定为HBV基因组前（pg） RNA封装的抑制剂，这是HBV生命周期的关键步骤。PgRNA是HBV DNA逆转录复制的模板，其被病毒DNA聚合酶封装成核衣壳对随后的病毒DNA合成至关重要。与目前fda批准的抑制HBV DNA聚合酶的抗病毒核苷类似物的机制不同，pgRNA组装成核衣壳代表了一个新的治疗靶点，应该补充目前的抗病毒药物。通过对591个磺胺酰苄酰胺衍生物进行广泛的构效关系（SAR）研究，我们已经获得了具有亚微摩尔抗病毒活性的化合物，其中最好的是DVR-23 （EC50 = 280 nM, EC90 = 860nM）。在这个一期项目中，我们建议进一步优化现有化合物的磺胺部分，以确定具有优越抗病毒，药代动力学和毒理学特征的先导物，并在体内HBV转基因小鼠模型中测试其抗病毒效果