A Phase I, Randomised, Double-blind, Placebo-controlled, Parallel-group Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Biomarkers of AZD3839 Including an Open-label Food Effect Group in Healthy Male and Female Volunteers of Non-childbearing Potential

The purpose of the study is to assess the safety, tolerability and blood concentration of AZD3839 following oral administration of single doses in healthy men and women of non-childbearing potential

开始日期2011-06-01

申办/合作机构

AstraZeneca PLC

100 项与 AZD-3839 相关的临床结果

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100 项与 AZD-3839 相关的转化医学

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100 项与 AZD-3839 相关的专利（医药）

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项与 AZD-3839 相关的文献（医药）

2021-05-24·Journal of Biomolecular Structure and Dynamics

A series of molecular modeling techniques to reveal selective mechanisms of inhibitors to β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) and β-site amyloid precursor protein cleaving enzyme 2 (BACE2)

Article

作者: Li, Shipeng ; Yu, Hualin ; Li, Jinghui ; Zhao, Hexiang ; Hao, Jiajia

Inhibition of β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been shown to be an effective treatment for Alzheimer's disease. A wealth of research has focused on finding highly selective small-molecule inhibitors targeting the BACE1 over its close homologue BACE2 to avoid potential side effects. However, given the highly structural similarities of BACE1 and BACE2, designing highly selective BACE1 inhibitors remains a huge challenge. Recently, it has been reported that a potential BACE1 inhibitor named C28 (∼52-fold selectivity) exhibited greater selectivity to BACE1 over BACE2 than the previously reported inhibitors AZD3293 and AZD3839 (∼1.5-fold and 14-fold selectivity). However, few computational studies have been performed to reveal its underlying mechanisms. In this study, a series of molecular modeling techniques were performed to reveal the selective mechanisms. Classical molecular dynamics (cMD) simulations indicated that the major variations appeared to be controlled by overall protein dynamics. Free energy calculations further suggested that the binding affinities of AZD3293 to BACE1 and BACE2 are similar, but the binding affinity of AZD3839 and C28 to BACE1 is much higher than to BACE2, and that the major variations are electrostatic interactions. The protein dynamics and energy differences were further observed in accelerated molecular dynamics (aMD) simulations. In addition, the umbrella sampling simulations revealed the inhibitors' different patterns of dissociation from the binding pockets of BACE1 and BACE2, and that different energy barriers were responsible for the selectivity. The physical principles revealed by this study may facilitate the rational design of more potent BACE1 selective inhibitors. Communicated by Ramaswamy H. Sarma.

2017-11-01·Analytical and Bioanalytical Chemistry2区 · 化学

A microfluidics-based mobility shift assay to identify new inhibitors of β-secretase for Alzheimer’s disease

2区 · 化学

Article

作者: Liu, Rongfeng ; Zhu, Haiyan ; Zhang, Xuehong ; Liu, Yu-Chih ; Meng, Junwei

The β-secretase (BACE1) initiates the generation of toxic amyloid-β peptide (Aβ) from amyloid-β precursor protein (APP), which was widely considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Here, a novel microfluidics-based mobility shift assay (MMSA) was developed, validated, and applied for the screening of BACE1 inhibitors for AD. First, the BACE1 activity assay was established with a new fluorescent peptide substrate (FAM-EVNLDAEF) derived from the Swedish mutant APP, and high-quality ratiometric data were generated in both endpoint and kinetic modes by electrophoretic separation of peptide substrate from the BACE1 cleaved product (FAM-EVNL) before fluorescence quantification. To validate the assay, the inhibition and kinetic parameter values of two known inhibitors (AZD3839 and AZD3293) were evaluated, and the results were in good agreement with those reported by other methods. Finally, the assay was applied to screen for new inhibitors from a 900-compound library in a 384-well format, and one novel hit (IC₅₀ = 26.5 ± 1.5 μM) was identified. Compared with the common fluorescence-based assays, the primary advantage of the direct MMSA was to discover novel BACE1 inhibitors with lower auto-fluorescence interference, and its superb capability for kinetic study. Graphical abstract Microfluidics-based mobility shift assay for BACE1.

2014-09-01·Clinical Pharmacology in Drug Development4区 · 医学

Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

4区 · 医学

Article

作者: Alexander, Robert ; Bueters, Tjerk ; Quartino, Angelica ; Karlsson, Pär ; Fälting, Johanna ; Lüttgen, Maria ; Sparve, Erik ; Lee, Chi‐Ming ; Paulsson, Björn ; Maltby, Justine ; Claeson‐Bohnstedt, Kristina ; Paraskos, Jonathan ; Huledal, Gunilla ; Olsson, Tina

AbstractModulating deposition of Aβ‐containing plaques in the brain may be beneficial in treating Alzheimer's disease. β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aβ in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Aβ40 and Aβ42, of the BACE1 inhibitor AZD3839 were evaluated.Single oral ascending doses (1–300 mg) of AZD3839 were administered to 54 young healthy volunteers in a randomized, double‐blind, placebo‐controlled study. The data was analyzed using non‐linear mixed effects modeling. AZD3839 reduced Aβ40 and Aβ42 in plasma with estimated potencies (EC50) of 46 and 59 nM, respectively, and a maximum effect of approximately 55%. This was in excellent agreement with the concentration–response relationships obtained in mouse and guinea pig. AZD3839 exposure displayed non‐linear kinetics, described by a three‐compartment model with a saturated binding compartment and an increase in bioavailability with dose. AZD3839 was safe, although, a dose‐dependent QTcF prolongation was observed (mean 20 milliseconds at 300 mg).In conclusion, AZD3839 reduced plasma Aβ40 and Aβ42, demonstrating clinical peripheral proof of mechanism. Pre‐clinical models were predictive for the effect of AZD3839 on the human plasma biomarker in a strictly quantitative manner.

项与 AZD-3839 相关的新闻（医药）

2022-07-02

·靶点社

阿尔茨海默症药物研发，Aβ、Tau、免疫、基因疗法百花齐放

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。引言作为认知最广泛的神经退行性疾病，阿尔茨海默症一直没有行之有效的治疗药物，6月3日，一篇发表在nature neuroscience上的文章揭示了阿尔茨海默症（Alzheimer's disease，AD）最可能接近真相的病因，溶酶体酸化障碍，但是，这和最终开发阿尔茨海默症的药物还有不小的距离。AD大脑神经病理学改变的特征包括，Aβ蛋白沉积形成的淀粉样蛋白斑，神经原纤维缠结（过度磷酸化tau蛋白组成的胞内聚集体），突触的丧失、萎缩、神经递质系统（例如乙酰胆碱）的选择性耗竭以及路易体（少数情况），以上这些情况导致了神经元之间的信息交流障碍甚至神经元的死亡，最终导致AD。因此目前的药物开发思路主要是围绕清除β样淀粉蛋白（Aβ蛋白），调节Tau蛋白，以及ACHE（乙酰胆碱酯酶抑制剂）等这些热门的领域，但是近年来也有一些新的AD机制和治疗方法兴起，比如炎症理论，干细胞疗法和基因疗法。阿尔茨海默病神经病理学包括含有无数淀粉样蛋白-β (Aβ) 寡聚体的细胞外淀粉样蛋白斑块和含有磷酸化tau的神经元内缠结。小胶质细胞和星形胶质细胞被激活，导致神经炎症和神经病理学的扩散。 Aβ蛋白级联假说Aβ蛋白是弥漫性和神经炎性斑块的主要蛋白质成分，其起源于淀粉样前体蛋白（APP）的蛋白水解。APP是一种1型整合跨膜蛋白，其结构中Aβ的C端部分嵌入细胞膜内。产生Aβ蛋白需要2个连续的蛋白水解步骤，先由β-分泌酶在Aβ序列的N末端区域切割APP，产生稍短的可溶性N末端（APPsβ）和淀粉样蛋白C末端片段（C99），β-分泌酶对C99的切割释放出APP的C端50个残基，称为APP胞内结构域（AICD）和Aβ。而在其分解过程中，细胞内的溶酶体承担了大部分的工作。溶酶体的酸化障碍导致细胞错误产生的Aβ蛋白不能正常被分解，进而撑破溶酶体，使得细胞破裂将Aβ蛋白释放到细胞外，进一步形成斑块。Aβ蛋白可以引发一系列的信号级联反应，研究发现，其可以通过以下几条途径降低突触可塑性（突触连接强度可调节的特性（神经递质释放、细胞接受突触的敏感型等））或减少突触的密度。1、与细胞朊病毒蛋白（PrPC）结合，激活Fyn激酶，然后通过NMDA型谷氨酸受体（NMDAR）途径开启对突触的长期抑制作用（LTD）。2、非NMDAR途径，与PrPC和代谢型谷氨酸5受体（mGlu5Rs）形成三元复合物，导致突触可塑性受损和突触的密度下降3、Aβ蛋白的积聚可间接性导致Tau蛋白在大脑区域中的累积和扩散。4、Aβ蛋白可以抑制乙酰胆碱受体（ACHR），诱导LTD，导致突触传导抑制。药物研发现状利用单克隆抗体结合细胞外的Aβ蛋白单体/可溶性的聚集体（目前最主流的方法），防止其聚合或者激发下游信号通路。代表性的药物有百健的aducanumab，礼来的donanemab和罗氏的crenezumab。但根据Aβ信号级联理论，在Aβ蛋白的产生，以及降解的过程，都有机会进行药物的研发。目前一些药物研发是针对APP产生Aβ蛋白过程中的β-分泌酶，研发其抑制剂（Beta secretase inhibitor/BACE），例如法兰克福大学的MH-84，默沙东的MBI-10，不过这些目前都处于临床前的研究阶段，距离成药还有一段不小的距离。也有一些其他的研究方向，比如Aβ聚集抑制剂（曲米酸、鲨肌醇、PBT2）Aβ抗原（AN-1792、vanutide、AD02、CAD-106）抗Aβ多克隆抗体（免疫球蛋白）γ-分泌酶抑制剂（begacestat、semagacestat和avagacestat）γ-分泌酶调节剂（tarenflurbil）β-位点淀粉样前体蛋白裂解酶（BACE）抑制剂（LY2811376、LY2886721、AZD3839、verubecestat、atabecestat和lanabecestat）。阻断其下游通路也可作为AD药物研发的新思路，比如今年6月1日发表在science上的一篇文章，揭示了mGlu5Rs的无声（SAM）变构调节剂（BMS-984923，百时美施贵宝）可以逆转阿尔茨海默小鼠的突触丢失。也有针对NMDAR途径研发的NMDA药物，虽然这种药物对改善神经认知的效果不错，但是容易引发抑郁。 Tau蛋白假说Tau是稳定神经元微管的微管相关蛋白（MAP）之一，主要出现在轴突中（与体树突MAP2相比）。神经元之间的信息传递依赖于微管作为轨道，而tau蛋白与微管相结合以维持其稳定性。当tau的关键位点磷酸化（主要是Ser262或Ser214），Tau则从已结合的微管中释放出来，导致微管破裂和tau聚集成成对的螺旋丝（PHF）。Tau高磷酸化和神经纤维缠结是AD病理学的关键组成部分，被认为由人类大脑的上游Aβ突触病理学驱动，并与Aβ协同增效以进一步的突触丢失。关键磷酸化位点Tau包含一个酸性N端结构域、一个碱性和富含脯氨酸的中间结构域、一个包含三个或四个内部重复的碱性结构域和一个C端结构域。它可以在多个位点被磷酸化，其中一些调节其微管结合特性。出现在内部重复序列两侧的两个区域中的几个Ser-Pro或Thr-Pro基序，对tau-微管相互作用只有中等影响，但可用作AD样tau磷酸化的诊断工具的。并且是脯氨酸定向激酶的靶标，例如糖原合酶激酶3、细胞周期蛋白依赖性激酶Cdk5或MAP激酶。其他位点包括蛋白激酶A（例如Ser214）、微管亲和调节激酶（MARK，在KXGS基序处，包括Ser262、Ser356）或Ca 2+ /钙调蛋白依赖性蛋白激酶（Ser416）的靶点。tau蛋白物研发思路许多异常磷酸化位点位于Ser-Pro或Thr-Pro基序上，因此针对AD-tau研发的各种抗体则是与这些磷酸化位点发生反应。免疫学说最近，全基因组关联研究表明，神经炎症的积累是介导AD开始和进展的遗传危险因素。在人类研究中，超过25个遗传位点与发生AD的风险有关，其中大多数主要在小胶质细胞中表达并与神经炎症有关。神经炎症可以促进Aβ蛋白的产生并且诱导tau的磷酸化。神经炎症及其下游通路Aβ斑块周围的小胶质被激活到促炎症状态，并分泌白细胞介素（IL）-1β。IL-1β促进神经元中可溶性淀粉样蛋白前体蛋白（sAPP）α的产生，sAPPα通过激活核因子kappa B（NF-κB）信号传导小胶质细胞中Pro-IL-1β的产生。同时，Aβ激活NLRP3炎症体，从灭活的Procaspase-1中产生激活的Caspase-1，导致小胶质细胞进一步分泌IL-1β。该循环使神经炎症事件成为慢性，并通过激活p38有丝分裂原激活蛋白激酶（p38-MAPK）途径诱导神经元中tau的高磷酸化和突触蛋白的减少。神经病理学研究假设的小胶质细胞在阿尔茨海默病（AD）中的代表性促炎症调节神经炎症的因子与AD神经炎症机制有关的调节因子有，骨髓细胞-2（TREM2）跨膜蛋白（其水解裂解的减少会加剧神经炎症，是大脑微胶质活动的调节剂），富含核苷酸结合域的亮氨酸重复序列（NLR）和含有pyrin结构域3（NLRP3），含有半胱天冬酶募集结构域（ASC）的凋亡相关斑点样蛋白（ASC）、CD33 和 CD22 。钙稳态调节剂在大脑中，小胶质细胞是最丰富的免疫细胞类型，占所有免疫细胞的80%以上。而钙稳态与小胶质细胞活化密切相关，Aβ增加细胞内钙水平，这反过来又有助于小胶质细胞中NLRP3炎症小体的活化。钙稳态调节剂家族蛋白（Calhm，Calhm1，Calhm2和Calhm3）的作用在AD研究领域受到越来越多的关注。在敲除Calhm2的小鼠中，其Aβ沉淀和神经炎症都显著降低，并减轻了AD相关的认知障碍。基因疗法ApoE4目前已经明确的和AD有关的基因是ApoE基因突变，特别是ApoE4基因，此基因的作用可以参考突破！Cell发表APOE4引发阿尔茨海默病的机制这篇文章。目前也有一些临床试验针对此基因展开。过氧化物酶体增殖剂激活受体γ共激活剂-1α（PGC-1α）PGC-1α主要参与调节β-APP切割酶1（BACE-1）的生产，该酶负责Aβ的生产。一项涉及接触hPGC-1α的APP23转基因小鼠的临床试验表明，小鼠的记忆力有所改善，淀粉样沉积物也有所减少。此外，由于NGF和脑源性神经营养因子的表达增加，还具有神经保护作用CRISPR/Cas9AD具有APP、PSEN1和PSEN2基因突变形式的易感性的遗传基础，它还与ApoE4等位基因的表达有关，这些基因位点可以作为治疗的靶点。目前已经有一些利用CRISPR的靶点治疗研究，具体如下：小结越来越多的证据表明，AD 是一种异质性疾病，由超出典型教条的各种病理生理机制引起。例如，多达三分之一的临床诊断为 AD 的患者没有 Aβ 积累，而许多在死后活检中诊断为 AD 的患者并没有表现出认知障碍。现今的理论认为，阿尔茨海默症可能和癌症一样，拥有不同的致病成因，因此识别AD的分子生物标志物以区分不同亚型，可能是开发出更有效的药物的关键，而未来差异化病因的阿尔兹海默症的治疗药物将会百花齐放。参考来源：[1] Alzheimer's disease: Aβ，tau and synapticdys function[2] Tau in Alzheimer's disease[3] Treatments for Alzheimer's disease emerge[4] Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q[5] Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer’s disease pathology[6] Sustained Trem2 stabilization accelerates microglia heterogeneity and Aβ pathology in a mouse model of Alzheimer’s disease[7] Roles of microglia in Alzheimer’s disease and impact of new findings on microglial heterogeneity as a target for therapeutic intervention[8] An update on Alzheimer's disease: Immunotherapeutic agents, stem cell therapy and gene editing[9] Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targetsPR 稿对接：邮箱 acgt@pharnex.com靶点社靶点江湖 · 新药际会PR | 品牌推广 | 会议会展 | 行业咨询靶点社ACGT「靶点社，汇聚50,000+创新药英雄」

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100 项与 AZD-3839 相关的药物交易

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