THE DINUCLEOTIDE SB-9000 A NOVEL ANTI-HBV AGENT

二核苷酸 SB-9000 一种新型抗 HBV 药物

• 批准号: 6734129
• 负责人: RADHAKRISHNAN P IYER
• 金额: $ 26.5万
• 依托单位: SPRING BANK TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6734129
• 关键词: antiviral agents; chemical synthesis; cooperative study; cytotoxicity; dinucleotide; disease /disorder model; drug design /synthesis /production; genetically modified animals; hepatitis B virus group; laboratory mouse; liver disorder chemotherapy; liver pharmacology; marmots; nonhuman therapy evaluation; oral administration; pharmacokinetics; prodrugs

DESCRIPTION (provided by applicant): The overall aim of this proposal is the development of SB-9000, a novel nucleotide analog, as an orally bioavailable anti-HBV therapeutic agent. The compound was discovered after synthesis, screening, and lead optimization, of a combinatorially-derived library of more than 700 nucleotides as potential inhibitors of HBV replication, using a cell-based assay. The analog displayed high antiviral potency, safety and selectivity indices. The compound inhibits both strands of HBV DNA replication. SB-9000 represents a new, and novel class of anti-HBV compound with demonstrated anti-HBV activity in vitro and efficacy in vivo in an HBV animal model. SB-9000 also shows synergistic anti-HBV activity with 3TC, is active against drug-resistant HBV variants, and has a novel mechanism(s) of action. The proposed studies will be carried out in two phases: Phase I involves (a) Process development for the synthesis of SB-9000, (b) Evaluation of SB-9000 in woodchuck HBV animal model (c) Design, synthesis and evaluation of prodrugs in vitro. Phase II involves (a) Metabolism, oral bioavailability, and pharmacokinetic studies of the prodrugs (b) Evaluation of the prodrugs in transgenic mouse and woodchuck HBV animal models (c) Scale-up and process transfer for GMP manufacture of the prodrug (d) IND-enabling in vitro and in vivo toxicity studies. Four developmental milestones have been set up and are as follows: (1) Process for larger-scale synthesis of SB-9000 (2) Selection of prodrug for in vitro and in vivo studies (3) Identification of orally bioavailable prodrug (4) Completion of IND-enabling studies for the drug candidate. The novel antiviral discovery and development strategy described in the proposal can be applied in the case of other existing and emerging viruses.

描述（由申请人提供）：本提案的总体目标是开发SB-9000（一种新型核苷酸类似物）作为口服生物可利用的抗HBV治疗剂。该化合物是在合成、筛选和先导优化后发现的，使用基于细胞的测定法，将700多个核苷酸的组合衍生文库作为HBV复制的潜在抑制剂。该类似物具有较高的抗病毒活性、安全性和选择性。该化合物抑制HBV DNA复制的两条链。SB-9000代表了一种新型的抗HBV化合物，在体外具有抗HBV活性，在HBV动物模型中具有体内疗效。SB-9000还显示出与3 TC的协同抗HBV活性，对耐药HBV变体具有活性，并具有新的作用机制。拟定的研究将分两个阶段进行：I期包括（a）SB-9000合成的工艺开发，（B）SB-9000在土拨鼠HBV动物模型中的评价（c）前药的体外设计、合成和评价。II期包括（a）前药的代谢、口服生物利用度和药代动力学研究（B）在转基因小鼠和土拨鼠HBV动物模型中评价前药（c）前药GMP生产的规模扩大和工艺转移（d）IND-使能的体外和体内毒性研究。已经建立了四个发展里程碑，如下：（1）SB-9000的大规模合成工艺（2）体外和体内研究前药的选择（3）口服生物可利用前药的鉴定（4）完成候选药物的IND使能研究。该提案中描述的新型抗病毒发现和开发策略可以应用于其他现有和新出现的病毒。