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Antiviral Res. 2020 Oct;182:104917. doi: 10.1016/j.antiviral.2020.104917. Epub 2020 Aug 17.
3
Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character.逃离平面世界：具有固有三维特征的取代桥连吡咯烷片段
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ACS Chem Biol. 2020 Jun 19;15(6):1708-1717. doi: 10.1021/acschembio.0c00320. Epub 2020 May 19.
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Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses and in Humanized Mice.新型乙型肝炎病毒衣壳组装调节剂诱导强烈的抗病毒反应和在人源化小鼠中。
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6
SAR studies in the sulfonyl carboxamide class of HBV capsid assembly modulators.HBV 衣壳组装调节剂磺酰羧酰胺类的 SAR 研究。
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7
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4-氧代辛可宁-1(2H)-甲酰胺作为乙型肝炎病毒 (HBV) 衣壳核心蛋白组装调节剂。

4-Oxooctahydroquinoline-1(2H)-carboxamides as hepatitis B virus (HBV) capsid core protein assembly modulators.

机构信息

Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA.

Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA; Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Pudong New District, Shanghai 200127, China.

出版信息

Bioorg Med Chem Lett. 2022 Feb 15;58:128518. doi: 10.1016/j.bmcl.2021.128518. Epub 2021 Dec 31.

DOI:10.1016/j.bmcl.2021.128518
PMID:34979256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8792325/
Abstract

Hepatitis B virus (HBV) core protein, the building block of the HBV capsid, plays multiple roles in viral replication, and is an attractive target for development of antiviral agents with a new mechanism of action. In addition to the heteroaryldihydropyrimidines (HAPs), sulfamoylbenzamides (SBAs), dibenzothiazepine derivatives (DBTs), and sulfamoylpyrrolamides (SPAs) that inhibit HBV replication by modulation of viral capsid assembly and are currently under clinical trials for the treatment of chronic hepatitis B (CHB), other chemical structures with activity to modulate HBV capsid assembly have also been explored. Here we describe our continued optimization of a benzamide originating from our high throughput screening. A new bicyclic carboxamide lead featuring an electron deficient non-planar core structure was discovered. Evaluations of its ADMET (absorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profiles demonstrate improved metabolic stability and good bioavailability.

摘要

乙型肝炎病毒 (HBV) 核心蛋白是 HBV 衣壳的构建模块，在病毒复制中发挥多种作用，是开发具有新作用机制的抗病毒药物的有吸引力的靶点。除了异芳基二氢嘧啶 (HAPs)、磺胺苯甲酰胺 (SBAs)、二苯并噻嗪衍生物 (DBTs) 和磺胺吡咯酰胺 (SPAs) 通过调节病毒衣壳组装来抑制 HBV 复制，目前正在临床试验中用于治疗慢性乙型肝炎 (CHB) 之外，还探索了其他具有调节 HBV 衣壳组装活性的化学结构。在这里，我们描述了我们对高内涵筛选中起源的苯甲酰胺的持续优化。发现了一种具有缺电子非平面核心结构的新型双环羧酰胺先导化合物。对其 ADMET（吸收、分布、代谢、排泄和毒性）和药代动力学 (PK) 特征的评估表明，其代谢稳定性得到改善，生物利用度良好。