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全球 2.58 亿人，每年导致 88 万人死亡肝硬化、肝细胞癌 (HCC) 和肝功能衰竭的现行治疗标准，包括药物治疗。调节宿主抗病毒免疫反应的聚乙二醇化干扰素α和抑制病毒的核苷（酸）类似物病毒DNA聚合酶，可以有效抑制病毒复制，但不能诱导HBV表面抗原丢失（HBsAg），成功的免疫控制或慢性乙型肝炎的功能性治愈的标志，在广泛的因此，开发具有新机制的新型抗病毒药物可以治疗大多数患者。激活宿主抗病毒免疫反应是实现慢性乙型肝炎功能性治愈所必需的 (CHB)。二氢喹嗪酮 (DHQ) RG-7834 是罗氏发现的一种小分子，可以快速减少乙型肝炎病毒 (HBV) RNA 水平，以及几乎所有病毒基因产物，包括 HBsAg。一种全新的 HBV 抗病毒药物化学型和一种控制 CHB 的新方法。 RG-7834 的神经毒性使其无法全身用于治疗慢性乙型肝炎。通过生产肝脏选择性和中枢神经系统难治性 DHQ 抗病毒药物可以最大限度地减少或消除这种影响。根据这一假设，我们最近设计并合成了一系列新型双羧酸基 DHQ 本系列中首次显示具有有机阴离子转运多肽 (OATP) 的衍生物底物特性，有利于化合物选择性分布到治疗作用位点（肝脏），相对于血流，这一努力导致了一种早期先导物质的发现，称为 DHQ-65042，它是在生化和细胞测定中均有效（HepG2.2.15 细胞系中 EC50 = 23 nM），同时证明与 RG-7834 相比，具有相当大的安全性改进潜力，例如低血脑屏障 (BBB) 渗透（体外测定）和体内肝脏对血浆的高选择性（小鼠 PK 中肝脏/血浆比率为 37.8）这一系列新颖的肝脏靶向 DHQ 有望通过有限的方式改善安全性。尽管 DHQ-65042 在体内暴露，但分布到血流、大脑和其他身体组织肝脏从口服途径进行的药代动力学（PK）研究是温和的，以验证该R21提案。开发新型肝脏靶向 DHQ 衍生物作为乙型肝炎病毒表面抗原还原剂的可行性实用价值，我们将进行先导物优化，以低剂量将肝脏暴露提高到有效水平维持血浆暴露，并确定肝选择性和胃肠道/肝脏之间的平衡窗口通过三个目标中提出的工作吸收新的线索将成功完成该项目。使我们能够开发新一代 DHQ，以足够的浓度选择性地递送至肝脏足以显着降低 HBsAg 并具有更好的安全性，并为体内提供新的先导药物毒性和功效研究。