THE DINUCLEOTIDE SB-9000 A NOVEL ANTI-HBV AGENT

描述(由申请人提供)：本提案的总体目标是开发SB-9000，一种新的核苷酸类似物，作为一种口服生物可用抗乙肝治疗剂。该化合物是在合成、筛选和先导优化后发现的，该文库由700多个核苷酸组合而成，使用基于细胞的分析方法作为潜在的乙肝复制抑制剂。该类似物具有较高的抗病毒效力、安全性和选择性指数。该化合物抑制HBVdna复制的两条链。SB-9000是一种新的、新型的抗乙肝病毒化合物，具有体外抗乙肝病毒活性和体内抗乙肝病毒动物模型的效果。SB-9000还显示出与3TC的协同抗乙肝病毒活性，对耐药的乙肝病毒变异株具有活性，并具有新的作用机制(S)。拟议的研究将分两个阶段进行：第一阶段涉及(A)合成SB-9000的工艺开发，(B)在土拨鼠乙肝动物模型中评价SB-9000，(C)体外前药的设计、合成和评价。第二阶段包括(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的乙肝动物模型中对前药的评价(C)用于GMP生产的放大和工艺转移(D)体外和体内的IND毒性研究。已经建立了四个发展里程碑：(1)SB-9000的大规模合成工艺(2)体内外研究用前药的选择(3)口服生物利用型前药的鉴定(4)候选药物的IND使能研究完成。建议中描述的新的抗病毒发现和开发战略可以应用于其他现有和新出现的病毒的情况。

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.