THE DINUCLEOTIDE SB-9000 A NOVEL ANTI-HBV AGENT

描述（由申请人提供）：本申请的总体目标是开发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，该组合衍生文库包含超过700个核苷酸，使用基于细胞的测定方法作为HBV复制的潜在抑制剂。该类似物具有较高的抗病毒效力、安全性和选择性指标。该化合物抑制HBV DNA的两条链复制。SB-9000是一种新型的抗HBV化合物，在HBV动物模型中具有体外抗HBV活性和体内有效性。SB-9000还与3TC具有协同抗HBV活性，对耐药HBV变异具有活性，具有新的作用机制。拟议的研究将分两个阶段进行：第一阶段涉及(a) SB-9000的合成工艺开发，(b) SB-9000在土拨鼠HBV动物模型中的评价(c)前体药物的体外设计、合成和评价。II期涉及(a)前药的代谢、口服生物利用度和药代动力学研究(b)前药在转基因小鼠和土拨鼠HBV动物模型中的评估(c)前药GMP生产的放大和工艺转移(d) IND-enabling体外和体内毒性研究。建立了四个发展里程碑，分别是：(1)SB-9000的大规模合成过程(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研究。本提案所述的新型抗病毒药物发现和开发策略可应用于其他现有和新出现的病毒。

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.