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

摘要 二氢喹诺酮RG-对宿主RNA质控酶PAPD5和PAPD7的抑制作用 7834(DHQ-1)是一种小分子，它能迅速降低乙肝病毒(HBVRNA)水平，因此 几乎所有的病毒基因产品，包括乙肝表面抗原。这代表了一个全新的乙肝病毒类别 抗病毒药物。但DHQ-1的神经毒性观察限制了其全身应用的程度。 慢性乙型肝炎(CHB)的管理。这种副作用可以通过以下方法最小化或消除 生产肝脏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 当前专利之外的一系列新的双羧酸基DHQ衍生物 描述。它们具有有机阴离子转运多肽(OATP)底物特性， 这促进了化合物选择性地分布到治疗作用部位(肝脏) 相对于血液流动。这些E-ff发现了早期的铅DHQ-E-OH(3)， 它在生化和细胞分析中都很有效，同时显示出相当的安全性 改善，如低血脑屏障(BBB)穿透潜力和较高的肝脏 与DHQ-1相比，DHQ-1对血浆的选择性(PK研究中肝脏/血浆比率为37.8)。然而， 早期的铅3被发现是通过口服低水平吸收的，可能是因为它的低水平。 亲油性。因此，第一阶段的建议是建立在这一发现的基础上，并确定甚至 更有效的DHQ衍生物，具有更平衡的肝脏选择性和渗透性，可以 产生，从而在增加肠道功能的情况下保持对PAPD5&7和乙肝表面抗原的有效抑制 吸收的同时保持良好的肝靶向选择性和低的血脑屏障渗透风险。 通过迭代结构--ADME优化，得到了该材料的允许透气性窗口 将对一系列化合物进行调查。新化合物将在体外进行测试。 和体内药效学模型的能力，以降低乙肝表面抗原，血脑屏障 渗透性，维持较高的肝脏趋向性和肝脏/血浆分布比率，最重要的是， 增加在肝脏中的浓度和停留时间，但不会导致肝脏和轴突的形成 毒性。符合这些特定标准的化合物将被推进到STTR第二阶段 药效和毒性的研究。

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.