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

基本信息

  • 批准号:
    10384184
  • 负责人:
  • 金额:
    $ 30万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
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Yanming Du其他文献

Yanming Du的其他文献

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{{ truncateString('Yanming Du', 18)}}的其他基金

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
  • 批准号:
    10593566
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Hepatoselective Dihydroquinolizinone (HS-DHQ) Molecules for Treatment and Prevention of Hepatitis A Virus (HAV) Infection
用于治疗和预防甲型肝炎病毒 (HAV) 感染的肝选择性二氢喹嗪酮 (HS-DHQ) 分子
  • 批准号:
    10698516
  • 财政年份:
    2023
  • 资助金额:
    $ 30万
  • 项目类别:
Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors
乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估
  • 批准号:
    9031576
  • 财政年份:
    2014
  • 资助金额:
    $ 30万
  • 项目类别:
Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors
乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估
  • 批准号:
    8850811
  • 财政年份:
    2014
  • 资助金额:
    $ 30万
  • 项目类别:
Evaulation of therapeutic benefits of HBV nucleocapsid assembly inhibitors
乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估
  • 批准号:
    8766392
  • 财政年份:
    2014
  • 资助金额:
    $ 30万
  • 项目类别:
Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors
乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估
  • 批准号:
    9282559
  • 财政年份:
    2014
  • 资助金额:
    $ 30万
  • 项目类别:
Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors
乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估
  • 批准号:
    9069416
  • 财政年份:
    2014
  • 资助金额:
    $ 30万
  • 项目类别:

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