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