4-oxooctahydroquinoline-1(2H)-carboxamides 作为乙型肝炎病毒 (HBV) 衣壳

StephenW

4-oxooctahydroquinoline-1(2H)-carboxamides 作为乙型肝炎病毒 (HBV) 衣壳核心蛋白组装调节剂
Nicky Hwang 1，Haiqun Ban 2，Suo Wu 1，Kelly McGuire 3，Ellen Hernandez 4，Junjun Chen 1，Qong Zhao 1，Manasa Suresh 5，Benjamin Blass 6，Usha Viswanathan 1，John Kulp 1，Jason Clement 1 1 , Stephan Menne 5 , Ju-Tao Guo 1 , Yanming Du 1
隶属关系
隶属关系

    1
    Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA。
    2
    Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA;上海交通大学医学院附属仁济医院，上海市浦东新区东方路1630号，200127。
    3
    天普大学，1801 N Broad St，宾夕法尼亚州费城，191222，中国。
    4
    特拉华河谷大学，700 E Butler Ave, Doylestown, PA, 18901, 中国。
    5
    乔治城大学医学中心，3900 Reservoir Road，华盛顿特区，20057，中国。
    6
    天普大学药学院药学系 3307 North Broad Street, Philadelphia, PA, 19140, 中国。

    PMID：34979256 DOI：10.1016/j.bmcl.2021.128518

抽象的

乙型肝炎病毒 (HBV) 核心蛋白是 HBV 衣壳的组成部分，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目标。除了通过调节病毒衣壳组装来抑制 HBV 复制的杂芳基二氢嘧啶 (HAP)、氨磺酰苯甲酰胺 (SBAs)、二苯并硫氮杂衍生物 (DBT) 和氨磺酰吡咯酰胺 (SPA) 之外，目前正在进行治疗慢性乙型肝炎 (CHB) 的临床试验)，其他具有调节 HBV 衣壳组装活性的化学结构也已被探索。在这里，我们描述了我们对源自我们的高通量筛选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甲酰胺铅。对其 ADMET（吸收、分布、代谢、排泄和毒性）和药代动力学 (PK) 曲线的评估表明，其代谢稳定性得到改善并具有良好的生物利用度。

版权所有 © 2021 Elsevier Ltd。保留所有权利。

StephenW

4-oxooctahydroquinoline-1(2H)-carboxamides as Hepatitis B Virus (HBV) Capsid Core Protein Assembly Modulators
Nicky Hwang  1 , Haiqun Ban  2 , Shuo Wu  1 , Kelly McGuire  3 , Ellen Hernandez  4 , Junjun Chen  1 , Qiong Zhao  1 , Manasa Suresh  5 , Benjamin Blass  6 , Usha Viswanathan  1 , John Kulp  1 , Jinhong Chang  1 , Jason Clement  1 , Stephan Menne  5 , Ju-Tao Guo  1 , Yanming Du  1
Affiliations
Affiliations

    1
    Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA.
    2
    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.
    3
    Temple University, 1801 N Broad St, Philadelphia, PA, 191222, China.
    4
    Delaware Valley university, 700 E Butler Ave, Doylestown, PA, 18901, China.
    5
    Georgetown University Medical Center, 3900 Reservoir Road, Washington, DC, 20057, China.
    6
    Temple University School of Pharmacy, Department of Pharmaceutical Sciences 3307 North Broad Street, Philadelphia, PA, 19140, China.

    PMID: 34979256 DOI: 10.1016/j.bmcl.2021.128518

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.

Copyright © 2021 Elsevier Ltd. All rights reserved.

小牡丹

不从乙肝自愈者入手的乙肝治愈药物研究，都是不自量力，成功几率很低，可以忽略不计，就像一个不会走路的孩子参加马拉松一样可笑。