Developing Hepatoselective Hepatitis B Therapeutic Dihydroquinolizinone (DHQ) Molecules with Better Safety Profiles for Efficient HBsAg Reduction

开发具有更好安全性的肝选择性乙型肝炎治疗二氢喹嗪酮 (DHQ) 分子，可有效降低 HBsAg

• 批准号: 10384184
• 负责人: Yanming Du
• 金额: $ 30万
• 依托单位: HARLINGENE LIFE SCIENCES LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384184
• 关键词: Acids; Antiviral Agents; Biochemical; Biochemistry; Biological Assay; Blood; Carboxylic Acids; Categories; Cell Line; Cellular Assay; Chronic Hepatitis B; Dose; Enzymes; Esters; HepG2; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Therapy; Hepatitis B Virus; Hepatotoxicity; Intestinal Absorption; Kinetics; Lead; Legal patent; Liver; Measurement; Medicine; Metabolic; Mus; Neurites; OATP Transporters; Oral Administration; Permeability; Pharmaceutical Preparations; Phase; Plasma; Positioning Attribute; Preventive; Primary carcinoma of the liver cells; Prodrugs; Property; Quality Control; RNA; Refractory; Residencies; Risk; Safety; Series; Site; Small Business Technology Transfer Research; Solubility; Stream; Structure; Testing; Therapeutic; Time; Toxic effect; Tropism; Vaccines; Viral Proteins; analog; base; blood-brain barrier penetration; cytotoxicity; design; efficacy study; in vitro Assay; in vivo; lipophilicity; mortality; neurotoxicity; novel; pharmacodynamic model; phase 2 study; side effect; small molecule; uptake; viral RNA

ABSTRACT Inhibition of the host RNA quality control enzymes, PAPD5 & 7, with a Dihydroquinolizinone RG- 7834 (DHQ-1), a small molecule, rapidly reduces hepatitis B virus (HBV) RNA levels, and hence almost all viral gene products, including HBsAg. This represents an entirely new category of HBV antivirals. But observation of neurotoxicity of DHQ-1 limits the degree of systemic use for management of chronic hepatitis B (CHB). This side effect can be minimized or eliminated by producing liver selective and CNS refractory DHQ antivirals. We have designed and synthesized a novel series of bis-carboxylic acid based DHQ derivatives that are outside current patent descriptions. They have organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds to the therapeutic site of action (liver) relative to the blood stream. These efforts led to the discovery of an early lead DHQ-E-OH (3), which is potent in both biochemical and cellular assays, while demonstrating considerable safety improvements such as low blood-brain barrier (BBB) penetration potential and higher liver selectivity over plasma (liver/plasma ratio is 37.8 in PK study) in contrast to DHQ-1. However, the early lead 3 was found to be absorbed via oral administration at a low level, likely due to its low lipophilicity. This Phase I proposal is therefore to build on this discovery and determine if even more efficacious DHQ derivatives with more balanced hepatoselectivity and permeability, can be produced, so that they retain potent inhibition of PAPD5 & 7 and HBsAg with increased intestinal absorption while maintaining the good liver targeting selectivity and low BBB penetration risk. Through an iterative structure-ADME optimization, the allowed window for the permeability of this series of compounds will be investigated. The new compounds will be tested in in vitro assays and in vivo pharmacodynamic models for their ability to reduce HBsAg, blood-brain barrier penetration, maintain high liver tropism and liver/plasma distribution ratios, and most importantly, increase the concentration and residency time in liver but not causing liver and neurite formation toxicity. Compounds that meet these specific criteria will be advanced to the STTR Phase II studies of efficacy and toxicity.

摘要 用二氢喹嗪酮RG抑制宿主RNA质量控制酶PAPD 5和7 7834（DHQ-1）是一种小分子，可迅速降低B型肝炎病毒（HBV）RNA水平，因此 几乎所有的病毒基因产物，包括HBsAg。这代表了一个全新的HBV类别 抗病毒药但是DHQ-1的神经毒性的观察限制了全身使用的程度， 慢性B型肝炎（CH B）的管理。这种副作用可以通过以下方式最小化或消除： 生产肝选择性和中枢神经系统难治性DHQ抗病毒药物。我们设计并合成了 一系列新的基于双羧酸的DHQ衍生物，其在当前专利范围之外， 描述。它们具有有机阴离子转运多肽（OATP）底物性质， 其促进化合物选择性分布至治疗作用部位（肝脏） 相对于血流。这些发现导致了早期铅DHQ-E-OH（3）的发现， 其在生物化学和细胞测定中均是有效的， 改善，如低血脑屏障（BBB）渗透潜力和更高的肝脏 与DHQ-1相比，对血浆的选择性（PK研究中肝脏/血浆比为37.8）。但 早期的铅3被发现通过口服以低水平吸收，可能是由于其低水平， 亲脂性因此，第一阶段的建议是建立在这一发现的基础上， 具有更平衡的肝选择性和渗透性的更有效的DHQ衍生物， 产生，因此它们保留PAPD5&7和HBsAg的有效抑制， 在保持良好的肝靶向选择性和低BBB渗透风险的同时， 通过迭代的结构ADME优化，可以确定这种结构的渗透率的允许窗口。 将研究一系列化合物。新化合物将在体外试验中进行测试 和体内药效学模型，以评估其降低HBsAg、血脑屏障 渗透，保持高的肝向性和肝/血浆分布比，最重要的是， 增加在肝脏中的浓度和停留时间，但不引起肝脏和神经突形成 毒性符合这些特定标准的化合物将进入STTR第二阶段 疗效和毒性研究。