Selection of the Optimal Nucleoside Triphosphate Mimic Prodrug Inhibitor of HCV R

HCV R 最佳核苷三磷酸模拟前药抑制剂的筛选

• 批准号: 8121945
• 负责人: PHILLIP DAN COOK
• 金额: $ 30万
• 依托单位: R. I. CHEMICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121945
• 关键词: 7-deazaguanosine; Adenosine; Antiviral Agents; Biological Availability; Clinical; Clinical Trials; Data; Development; Diffusion; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Industry; Drug Kinetics; Exhibits; FDA approved; Failure; Generic Drugs; Genotype; Growth; Guanosine; Guanosine Monophosphate; Half-Life; Hepatitis C; Hepatitis C virus; Human; Human Cell Line; In Situ; In Vitro; Interferons; Literature; Liver; Marketing; Modification; Nucleosides; Oral; Pharmaceutical Preparations; Phase; Plasma Proteins; Polymerase; Population; Preclinical Drug Development; Process; Prodrugs; Protease Inhibitor; Protein Binding; Replicon; Reporting; Resources; Ribavirin; Ribonucleosides; Scheme; Serum; Small Business Innovation Research Grant; Specificity; Structure-Activity Relationship; System; Therapeutic; Tissues; Toxic effect; Translational Research; Treatment Protocols; Vertebral column; Virus Inhibitors; Virus Replication; analog; anti-hepatitis C; base; cytotoxicity; drug candidate; drug discovery; inhibitor/antagonist; innovation; interest; novel; nucleoside monophosphate; nucleoside triphosphate; pre-clinical; standard of care; sugar; tripolyphosphate; uptake

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is a globally devastating disease. Beyond the limited efficiency combination treatment of 1-interferon (native or pegylated) and the nucleoside Ribavirin, which was introduced in 1990, there has not been another drug registered in the following 20 years. HCV NS5B polymerase is a validated target essential to virus replication. Currently, after the failure of several nucleosides and nucleoside prodrugs in HCV clinical trials, five nucleoside monophosphate prodrugs that target the NS5B polymerase are in HCV clinical trials. In this application, we will demonstrate that delivery of stabilized species of activated triphosphates of nucleosides (nucleoside triphosphate mimics, N3PMs) as prodrugs (N3PM-PDs) will be superior as inhibitors of HCV replication to those corresponding nucleosides, nucleoside prodrugs and nucleoside monophosphate prodrugs that have entered clinical trials. To accomplish this, we introduce several innovations in this application. 1) a structure- activity-relationship (SAR) study will identify the most active (against HCV NS5B polymerases) and selective (with lack of activity towards human polymerases) ribofuranosyl-triphosphate (2,3-CF2-P-1-P-modified-3'-obligate modified ribofuranosyl) hetero-bases; 2) obligate chain-termination ribofuranosyl moieties will be explored rather than the popular 2'-C-Me ribofuranosyl sugar employed by current clinical nucleosides; 3) a non-Watson/Crick, non-ionic, lipophilic, alternative hetero-base will be initially examined; 4) the optimized ribofuranosyl-triphosphate (2,3-CF2-P-1-P-modified-3'-obligate modified ribofuranosyl) will be generic for inhibition of HCV NS5B. Thus, various hetero-bases (heterocycles) conjugated to the SAR optimized ribofuranosyl-triphosphate can be examined; and 5) FDA-approved pivaloyloxymethyl (POM) prodrugs of these N3PMs will allow passive diffusion uptake and intracellular delivery of high concentrations of active species of N3PMs. Clearly, other literature ribofuranosyl nucleobases exhibiting interesting anti-HCV activity could be examined by our discovery process. For AIM 1 of this proposal, we consider the clinically validated POM moiety as a "generic" prodrug for N3PMs. Its use will allow structure-activity relationship studies in HCV replicons to move as rapidly as possible to determine the optimal 1-P and ribofuranosyl modifications of various hetero-bases. Optimizing the most effective prodrug will be a key AIM in a subsequent Phase 2 SBIR. In particular, consideration of liver-targeting prodrug moieties that may provide higher concentration of N3PMs in liver tissue will be explored. This approach alows us to move very rapidly, efficiently and economically in an effort to discover superior HCV inhibitors suitable for preclinical development, consistent with a recognized need for facilitated translational research. PUBLIC HEALTH RELEVANCE: Hepatitis C virus is global devastating disease, with minimal, effective therapeutics. We will demonstrate that the delivery of stabilized active species of nucleosides (nucleoside triphosphate mimics, N3PMs) as prodrugs (N3PM-PDs) will be superior as inhibitors of HCV replication than corresponding nucleosides, nucleoside prodrugs and nucleoside monophosphate prodrugs that have entered clinical trials. This approach allows us to move very rapidly, efficiently and economically in an effort to discover superior HCV inhibitors suitable for preclinical development, consistent with a recognized need for facilitated translational research.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染是一种全球毁灭性疾病。除了在1990年引入的1-Interferon（天然或pegypated）和核苷利巴韦林的有限效率联合处理外，在接下来的20年中没有另一种药物注册。 HCV NS5B聚合酶是对病毒复制必不可少的验证靶标。目前，在HCV临床试验中，几种核苷和核苷前药失败后，HCV临床试验中的五个核苷单磷酸前药是针对NS5B聚合酶的。在此应用中，我们将证明，作为前药（N3PM-PD）的核苷活化三磷酸的稳定物种（核苷三磷酸模拟物，N3PM）将是HCV复制的抑制剂，将其作为对相应的核苷，核苷前药和核苷单层磷酸盐的抑制剂的抑制剂。为此，我们在此应用程序中介绍了一些创新。 1）一项结构 - 活性关系（SAR）研究将确定最活跃的（针对HCV NS5B聚合酶）和选择性（缺乏对人类聚合酶的活性）核透明蛋白糖基 - 三磷酸（2,3-CF2-P-1-P-1-P-MODIFIED-3'- 3'-粘剂-3'-3'-粘法粉化的核苷酸核糖基）的核酸酯酶； 2）将探索强制性链终止核心基部分，而不是当前临床核苷使用的流行的2'-C-ME核透明糖基糖； 3）最初将检查一个非沃特森/克里克，非离子，亲脂性，替代性异源碱； 4）优化的核呋喃糖基 - 三磷酸（2,3-CF2-P-1-P-ratified-3'-粘合剂修饰的核呋喃糖基）将是抑制HCV NS5B的通用性。因此，可以检查与SAR优化的核透明蛋白糖基 - 三磷酸的各种杂碱基（杂环）。 5）这些N3PMS的FDA批准的pivaloyomoxymethyl（POM）前药将允许被动扩散吸收和高浓度的N3PM活性物种的细胞内递送。显然，我们的发现过程可以检查其他表现出有趣抗HCV活性的文献核呋喃糖基核碱。对于本提案的AIM 1，我们将经临床验证的POM部分视为N3pms的“通用”前药。它的使用将使HCV复制子中的结构活性关系研究尽可能迅速地移动，以确定各种异质碱基的最佳1-P和核透明素修饰。在随后的2阶段SBIR中，优化最有效的前药将是关键目标。特别是，将探索可能在肝组织中提供更高浓度的N3pm的肝脏靶向前药部分。这种方法使我们能够非常快速，有效，经济地移动，以发现适合临床前开发的优质HCV抑制剂，这与公认的促进转化研究需求一致。 公共卫生相关性：丙型肝炎病毒是全球毁灭性疾病，具有最少的有效治疗。我们将证明，作为前药（N3PM-PDS）作为前药（N3PM-PDS）的稳定活性物种（核苷三磷酸模拟物，N3PM）将是HCV复制的抑制剂，而不是相应的核苷，核苷前药物和核苷糖苷前药和单磷酸核苷磷酸盐磷酸盐的抑制剂。这种方法使我们能够非常快速，有效，经济地移动，以发现适合临床前开发的优质HCV抑制剂，这与公认的促进转化研究需求一致。