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.

抽象的 抑制宿主RNA质量控制酶，PAPD5和7，具有二氢喹啉酮Rg- 7834（DHQ-1），一个小分子，迅速降低丙型肝炎病毒（HBV）RNA水平，因此 几乎所有病毒基因产品，包括HBSAG。这代表了HBV的全新类别 抗病毒药。但是，DHQ-1神经毒性的观察限制了全身使用程度 慢性肝炎B（CHB）的管理。这种副作用可以最小化或消除 产生肝选择性和CNS难治性DHQ抗病毒药。我们设计和合成了 一系列新型的基于双羧酸的DHQ衍生物，这些衍生物是当前专利的 描述。他们具有有机阴离子运输多肽（OATP）底物特性， 该化合物的选定分布到治疗部位（肝） 相对于血流。这些效果导致发现了早期的铅DHQ-E-OH（3）， 这在生化和细胞测定中都具有潜力，同时证明了相当大的安全性 诸如低血脑屏障（BBB）渗透势和较高的肝脏等改善 与DHQ-1相比，血浆（PK研究中的肝脏/血浆比率为37.8）的选择性为37.8。但是， 发现早期铅3通过低水平的口服给药吸收，可能是由于其低 亲脂性。因此，该阶段的建议是在此发现的基础上建立的，并确定是否是否 具有更均衡的肝选择性和渗透性的更有效的DHQ衍生物可以是 产生，以便它们保留对PAPD5和7的潜在抑制和HBSAG，并增加了肠道 在维持良好的肝脏靶向选择性和低BBB渗透风险的同时抽象。 通过迭代结构-Adme优化，允许的渗透性窗口 将研究一系列化合物。新化合物将在体外测定中进行测试 和体内药效学模型，以减少HBSAG，血脑屏障的能力 渗透，维持高肝脏的肝脏和肝脏/血浆分布比，最重要的是 增加肝脏的浓度和停留时间，但不会引起肝脏和神经蛋白 毒性。符合这些特定标准的化合物将提出到STTR II期 效率和毒性的研究。