Liver Targeting Dihydroquinolizinone (DHQ) Molecules as Hepatitis B Virus Antivirals with Reduced Toxicity

肝脏靶向二氢喹嗪酮 (DHQ) 分子作为乙型肝炎病毒抗病毒药物，毒性降低

基本信息

批准号：
10593566
负责人：
Yanming Du
金额：
$ 24万
依托单位：
BARUCH S. BLUMBERG INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593566
关键词：
Acids Acute Address Animal Model Antiviral Agents Binding Proteins Biochemical Blood Brain Carboxylic Acids Cell Line Cellular Assay Cessation of life Chronic Chronic Hepatitis B Cirrhosis DNA-Directed DNA Polymerase Development Dose Drug Kinetics Elements Employment Equilibrium Evaluation Exposure to Fatty Acids Future Generations Goals HepG2 Hepatitis B Hepatitis B Surface Antigens Hepatitis B Therapy Hepatitis B Virus Hepatitis B e Antigens Hepatocyte Human Immune Immune response In Vitro Intestinal Absorption Intestines Lead Liver Liver Cirrhosis Liver Failure Liver Microsomes Medicine Mus OATP Transporters Oral Organ Parents Patients Pegylated Interferon Alfa Peripheral Nerves Permeability Persons Pharmaceutical Preparations Plasma Polynucleotide Adenylyltransferase Positioning Attribute Preventive Primary carcinoma of the liver cells Prodrugs Property Refractory Reporting Risk Route Safety Series Serum Site Stream Surface Antigens System Testing Therapeutic Time Tissues Toxic effect Transaminases Vaccines Viral Viral Proteins Viremia Virus Replication Work absorption analog animal efficacy anti-hepatitis B blood-brain barrier crossing blood-brain barrier penetration carbene curative treatments cytotoxicity design efficacy study gene product improved in vitro Assay in vivo inhibitor innovation lead optimization lipophilicity neurotoxicity novel novel strategies oxidation pre-clinical primary endpoint side effect small molecule standard of care therapy design tissue culture viral DNA viral RNA

项目摘要

ABSTRACT Hepatitis B virus chronically infects 258 million people worldwide and causes 880 thousand deaths annually due to cirrhosis, hepatocellular carcinoma (HCC) and liver failure. The current standard of care medications, including pegylated interferon alpha that regulates host antiviral immune response and nucleos(t)ide analogues that inhibit viral DNA polymerase, can potently suppress viral replication, but fail to induce the loss of HBV surface antigen (HBsAg), an indication of successful immune control or the functional cure of chronic hepatitis B, in the vast majority of the treated patients. Therefore, the development of novel antivirals with a new mechanism that can activate the host antiviral immune response is required to achieve the functional cure of chronic hepatitis B (CHB). A dihydroquinolizinone (DHQ) RG-7834, a small molecule discovered by Roche, can rapidly reduce hepatitis B virus (HBV) RNA levels, and hence almost all viral gene products, including HBsAg. This represents an entirely new chemotype of HBV antivirals and a new approach for CHB control. However, the observation of neurotoxicity in RG-7834 prohibits its systemic use for the management of CHB. We hypothesize that this side effect can be minimized or eliminated by producing liver selective and CNS refractory DHQ antivirals. In support of this hypothesis, we have recently designed and synthesized a novel series of bis-carboxylic acid based DHQ derivatives that are shown, for the first time in this series, to have organic anion transporting polypeptide (OATP) substrate properties, which facilitates selective distribution of the compounds to the therapeutic site of action (liver), relative to the blood stream. This eﬀort led to the discovery of an early lead, called DHQ-65042, which is potent in both biochemical and cellular assays (EC50 = 23 nM in HepG2.2.15 cell line), while demonstrating considerable safety improvement potential in comparison to RG-7834, such as low blood-brain barrier (BBB) penetration (in vitro assay) and high in vivo liver selectivity over plasma (liver/plasma ratio is 37.8 in a mouse PK study). This novel series of liver targeting DHQs are promising for improving safety profiles through limited distribution to the blood stream, the brain, and other body tissues, though the exposure of DHQ-65042 in the liver from the oral route of a pharmacokinetic (PK) study is moderate. In this R21 proposal, to validate the feasibility of developing novel liver targeting DHQ derivatives as hepatitis B virus surface antigen reducers with practical value, we will perform lead optimization to improve the liver exposure to an efficacious level with low exposure in plasma maintained, and identify a balance window between hepatoselectivity and GI/ liver absorption of new leads through the works proposed in three aims. Successful completion of this project will allow us to develop a new generation of DHQs that are selectively delivered to livers with concentrations sufficient enough to significantly reduce HBsAg and have better safety profiles, and to provide a new lead ready for in vivo toxicity and efficacy studies.

抽象的乙型肝炎病毒长期感染了全球2.58亿人，每年造成8.8万人死亡肝硬化，肝细胞癌（HCC）和肝衰竭。当前的护理药物标准，包括调节宿主抗病毒免疫响应和核（t）IDE类似物的pe节制干扰素α 病毒DNA聚合酶可以潜在地抑制病毒复制，但无法诱导HBV表面抗原的丧失（HBSAG），表明成功免疫控制或慢性丙型肝炎的功能治愈大多数治疗的患者。因此，开发具有新机制的新型抗病毒药激活宿主抗病毒药免疫反应是为了实现慢性肝炎的功能治愈（CHB）。二氢喹啉酮（DHQ）RG-7834（由Roche发现的小分子）可以迅速降低乙型肝炎病毒（HBV）RNA水平，因此几乎所有病毒基因产物，包括HBSAG。这代表 HBV抗病毒药和CHB控制的新方法是全新的。但是，观察 RG-7834中的神经毒性禁止其系统用来管理CHB。我们假设这一方通过产生肝选择性和CNS难治性DHQ抗病毒药，可以最大程度地减少或消除效果。支持在这个假设中，我们最近设计并合成了一系列新型的基于双羧酸的DHQ 在本系列中首次显示有机阴离子运输多肽（OATP）的衍生物底物特性，哪些设施选择性分布化合物到治疗部位（肝脏），相对于血流。这种效果导致发现了早期的铅，称为DHQ-65042，这是在生化和细胞测定中的潜力（EC50 = 23 nm Hepg2.2.2.15细胞系），同时证明与RG-7834相比，相当大的安全性改进潜力，例如低血脑屏障（BBB）渗透（体外评估）和高于血浆的体内肝选择性高（小鼠PK中的肝脏/血浆比为37.8 学习）。有望通过有限分布到血流，大脑和其他身体组织，尽管DHQ-65042在来自药代动力学（PK）研究的口服途径的肝脏中等。在此R21提案中，以验证作为乙型肝炎病毒表面抗原降低的新型肝脏靶向DHQ衍生物的可行性实用价值，我们将执行铅优化，以提高肝脏暴露于有效水平，低维持血浆中的暴露，并确定肝选择性和肝脏/肝脏之间的平衡窗口通过在三个目标中提出的作品中提出的新潜在客户抽象。成功完成该项目将允许我们开发新一代的DHQ，这些DHQ有选择地将其集中到肝脏足以显着降低HBSAG并具有更好的安全性配置文件，并为体内提供新的铅毒性和效率研究。