第三代4-H异丙基二氢嘧啶（HAP）类似物作为乙型肝炎病毒（HB

StephenW

J Med Chem. 2017 Mar 24. doi: 10.1021/acs.jmedchem.7b00083. [Epub ahead of print]
Discovery and Pre-Clinical Characterization of a 3rd Generation 4-H HeteroAryldihydroPyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors.Qiu Z, Lin X, Zhang W, Zhou M, Guo L, Kocer B, Wu G, Zhang Z, Liu H, Shi H, Kou B, Hu T, Hu Y, Huang M, Yan SF, Xu Z, Zhou Z, Qin N, Wang YF, Ren S, Qiu H, Zhang Y, Zhang Y, Wu X, Sun K, Zhong S, Xie J, Ottaviani G, Zhou Y, Zhu L, Tian X, Shi L, Shen F, Mao Y, Zhou X, Gao L, Young JA, Wu JZ, Yang G, Mayweg AV, Shen HC, Tang G, Zhu W.
AbstractDescribed herein are the discovery and structure-activity relationship (SAR) studies of the 3rd generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the 1st and 2nd generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD), and subsequently selected for further development as oral anti-HBV infection agent.


PMID:28339215DOI:10.1021/acs.jmedchem.7b00083

StephenW

J Med Chem。 2017年3月24日。doi：10.1021 / acs.jmedchem.7b00083。 [提前印刷]
第三代4-H异丙基二氢嘧啶（HAP）类似物作为乙型肝炎病毒（HBV）衣壳抑制剂的发现和临床前鉴定。
邱泽，林旭，张炜，周梅，郭洛，寇克B，吴G，张Z，刘昊，史昊，寇柏，胡，，胡Y，黄梅，严旭，徐泽，周泽，秦N Wang，，，iu iu Zhang Zhang Zhang Zhang Wu Wu Sun，，ie，，，，，，，，，ao ao ao ao ao ao ao ao Y，Zhou X，Gao L，Young JA，Wu JZ，Yang G，Mayweg AV，Shen HC，Tang G，Zhu W.
抽象

本文描述了以引入C6羧基作为新型HBV衣壳抑制剂的第三代4-H杂芳基二氢嘧啶（4-H HAP）的发现和结构 - 活性关系（SAR）研究。与第一代和第二代4-H HAP相比，这一新系列的4-H HAP显示出改善的抗HBV活性和更好的药物特性。类似物12（HAP_R01）与Cp149 Y132A突变体六聚体的X射线晶体学研究清楚地阐明了C6羧基对增加的结合亲和力的作用，其形成与衣壳蛋白和配位水的强氢键相互作用。代表性的类似物10（HAP_R10）在体外（ADMET）和体内（小鼠PK和PD）中被广泛表征，随后选择作为口服抗HBV感染剂进一步开发。

PMID：
    28339215
DOI：
    10.1021 / acs.jmedchem.7b00083

newchinabok

感谢分享，核衣壳抑制剂就需要一点运气就成功

StephenW

中国罗氏研究人员
Xie, Jianxun; Roche Pharma Research and Early Devel
Opment, Roche
Innovation Center Shanghai
Ottaviani, Giorgio; Roche Pharma Research and Early
Development, Roche
Innovation Center Shanghai
Zhou, Yuan; Roche Pharma Research and Early Develop
Ment, Roche
Innovation Center Shanghai
Zhu, Lina; Roche Pharma Research and Early Developm
Ent, Roche
Innovation Center Shanghai
Tian, Xiaojun; Roche Pharma Research and Early Deve
Lopment, Roche
Innovation Center Shanghai
Shi, Liping; Roche Pharma Research and Early Develo
Pment
Shen, Fang; Roche Pharma Research and Early Develop
Ment
Mao, Yi; Roche Pharma Research and Early Developmen
T
Zhou, Xue; Roche Pharma Research and Early Developm
Ent
Gao, Lu; Roche Pharma Research and Early Developmen
T, Roche
Innovation Center Shanghai
Young, John; Roche Pharma Research & & lt; / RTI & gt;
Ent, Roche
Innovation Center Basel,
Wu, Jim; Ark Biosciences
Yang, Guang; Roche Pharma Research and Early Develo
Pment
Mayweg, Alexander; Versant Ventures,
Shen, Hong; Roche R & D Center China, Medicinal chemi
Stry
Tang, Guozhi, Ascentage Pharma,
Zhu, Wei; Senior Scientist, Medicinal Chemistry Ro
Che Pharma Research
And Early Development, Roche Innovation Center Shan
Ghai
谢建勋罗氏制药研究与早期研究
Opment，罗氏
上海创新中心
Ottaviani，Giorgio;罗氏制药研究与早期
发展，罗氏
上海创新中心
周元罗氏制药研究与早期发展
明特，罗氏
上海创新中心
朱丽娜罗氏制药研究与早期发展
Ent，罗氏
上海创新中心
田小军;罗氏制药研究与早期发展
Lopment，罗氏
上海创新中心
石立平罗氏制药研究与早期发展
皮特
沉芳芳罗氏制药研究与早期发展
注意
毛一义罗氏制药研究与早期发展
T
周，薛;罗氏制药研究与早期发展
Ent
高鲁罗氏制药研究与早期发展
T，罗氏
上海创新中心
年轻人约翰罗氏制药研究＆ （1）。
Ent，罗氏
巴塞尔创新中心
吴，吉姆方舟生物科学
杨光光罗氏制药研究与早期发展
皮特
梅维格，亚历山大; Versant风险投资公司，
沉宏;中国罗氏研发中心，药用化学
Stry
唐国志，Ascentage Pharma，
朱伟伟高级科学家，药物化学
Che Pharma研究
和早期发展，罗氏创新中心山
Ghai

StephenW

HBV capsid is formed by the assembly of HBV core proteins and it protects the enclosed viral genome and creates the environment for reverse transcription of pregenomic RNA (pgRNA) to DNA.
The assembly and disassembly of HBV capsids are essential steps in the HBV life cycle and interruptionof the normal capsid assembly process will block the HBV replication.6
There are several classes of HBV capsid assembly effectors reported to date with two distinct mechanism of actions. Most of the known capsid  assembly  effectors  including  compound 1  (AT-130)7, 2  (DVR-23)8  and  NVR  3-778  (structure
unknown)9 act as HBV pgRNA encapsidation blockers by accelerating the assembly of normal-sized but empty  capsids.10,11  By  contrast,  the  Heteroaryldihydropyrimidine  (HAP)  compounds  represented  by compound 3
(Bay 41-4109)6 is a unique chemical class of capsid assembly inhibitor, which can prevent the  normal  assembly  of  core  proteins  and  lead  to  an  aberrant  formation  of  capsid.  The  misassembled capsid will be subsequently degraded by host proteasomes.6, 12
Thus, the misassembly and depletion of HBV  core  proteins  result  in  the  inhibition  of  HBV  replication.  Moreover,  it  is  hypothesized  that  the depletion of core proteins may suppress the function of viral covalently closed circular DNA (cccDNA)
13 and help restore the innate immune response.14, 15
HAPs thus represent a promising chemical class of anti-HBV  agents  with  the  potential  to  be  the  first  new  direct  acting  anti-HBV  agent  since  the  launch  of
nucleosides in 1998. However, the current HAPs have not been optimized in terms of drug-ike properties for oral antiHBV treatment and there is a significant need existing for the discovery of new HAPs with improved anti-HBV activity, pharmacokinetic and safety profiles for clinical use.
In this article, we describe the design and discovery of a new generation of 4-H HAPs featuring the introduction of a C6 carboxyl group with improved anti-HBV activity and better drug-like properties.
Furthermore, the elaboration of this chemical series culminates in a potential clinical candidate selection.
通过组装HBV核心蛋白形成HBV衣壳，并保护封闭的病毒基因组，并为DNA前体基因组RNA（pgRNA）的逆转录创建环境。
HBV衣壳的组装和拆卸是HBV生命周期中的重要步骤，正常衣壳装配过程的中断将阻止HBV复制。
目前有几种类型的HBV衣壳装配效应器报告了两种截然不同的作用机制。大多数已知的衣壳装配效应器包括化合物1（AT-130）7,2（DVR-23）8和NVR 3-778（结构
未知）9通过加速正常大小但空的衣壳的装配，作为HBV pgRNA包封阻断剂.10,11相比之下，由化合物3表示的杂芳基二氢嘧啶（HAP）化合物
（Bay 41-4109）6是一种独特的化学类型的衣壳装配抑制剂，可以防止核心蛋白的正常组装，并导致衣壳异常形成。宿主蛋白酶体被错配的衣壳随后降解
因此，HBV核心蛋白质的错配和消耗导致HBV复制的抑制。此外，假设核心蛋白的消耗可能抑制病毒共价闭合环状DNA（cccDNA）的功能，
13，帮助恢复先天免疫反应14，15
因此，HAP代表了一种有希望的化学类别的抗HBV药物，可能是自推出以来首例新的直接作用的抗HBV药物
然而，目前的HAP在口服抗HBV治疗的药物性质方面尚未得到优化，并且对于发现具有改善的抗HBV活性，药代动力学和安全性概况的新HAP有显着的需要用于临床使用。
在本文中，我们描述了新一代4-H HAP的设计和发现，其特征在于引入具有改善的抗HBV活性和更好的药物样性质的C6羧基。
此外，该化学系列的阐述最终导致潜在的临床候选人选择。

灵魂不屈

感谢分享！