CN116782900A - Axl抑制剂slc-391作为抗病毒治疗药剂的用途 - Google Patents
Axl抑制剂slc-391作为抗病毒治疗药剂的用途 Download PDFInfo
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Abstract
本文提供了使用式(1)的AXL抑制剂的抗病毒疗法,其具有以下结构:
Description
技术领域
本公开提供了使用AXL激酶抑制剂治疗包括COVID-19的病毒感染性疾病的抗病毒疗法。
背景技术
AXL是受体酪氨酸激酶的TAM(Tyro3、AXL和MER)家族的成员。它是一种跨膜受体(分子量:100和140kDa),其包含细胞外(N端)结构域和细胞内(C端)酪氨酸激酶结构域。TAM家族在正常成人组织和器官***中起稳态调节因子作用。
AXL激活可以通过配体依赖性或配体非依赖性受体二聚化来介导。生长停滞特异性蛋白6(Gas6)已经被确定为结合AXL的细胞外结构域的主要配体,导致Gas6/AXL复合物的二聚化,并且导致AXL的细胞内酪氨酸激酶结构域上酪氨酸残基的自磷酸化。这些细胞内结构域的磷酸化随后触发下游信号传导通路,包括P13K-AKT-mTOR、MEK-ERK、NF-κB和JAK/STAT(Gay 2017;Wium 2018Schoumacher和Burbridge 2017)。AXL是对肿瘤的发展、生长和扩散以及免疫调节至关重要的多种细胞过程的推定驱动力(Schoumacher和Burbridge2017),使AXL成为抗癌治疗药物的开发的有希望的靶点。
此外,AXL是I型干扰素响应的关键抑制因子,并且被病毒靶向以阻断抗病毒免疫。已知AXL被若干种不同的包膜病毒使用,包膜病毒包括痘病毒、逆转录病毒、黄病毒、沙粒病毒、丝状病毒和α病毒(Shimojima 2006、Meertens 2012、Dowall 2016、Meertens 2017)。许多包膜病毒在其膜上展示磷脂酰丝氨酸,通过磷脂酰丝氨酸,它们结合GAS6和蛋白S,然后蛋白S结合至AXL。经由GAS6-AXL结合的病毒颗粒通过其酪氨酸激酶结构域有效地激活信号转导,以抑制I型干扰素(IFN)信号传导,并且促进病毒复制(Bhattacharyya 2013,Meertens 2017)。AXL通过两种机制增加病毒感染,即通过“凋亡拟态”增强病毒进入和抑制抗病毒I型干扰素响应。
AXL信号传导经由SOCS1/3和TBK1抑制病毒诱导的IFN响应(Sharif 2006,Cruz2019),导致受感染的细胞中病毒复制增加,并且降低邻近细胞的病毒防御(Huang 2015,Chen 2018,Strange 2019)。AXL是独特的I型干扰素响应检测点。IFNR信号传导诱导AXL表达。AXL是骨髓细胞(树突状细胞、巨噬细胞)、NK细胞和肿瘤细胞中TLR诱导的I型干扰素(IFN)响应的关键负反馈调节机制(Rothlin 2007,Lee 2019,Canadas2018)。
治疗性AXL受体抑制改善了实验模型中由原发性病毒感染导致的肺部病理,包括AXL在肺部内的重要作用(Shibata,2014)。在原发性呼吸道合胞病毒(RSV)感染期间,AXL抑制增加了产生IFN-γ的T细胞和NK细胞的数量,抑制了RSV复制和全肺IL-4和IL-13水平。通过AXL抑制作用降低了肺内H1N1感染炎症的致死效应。受感染的小鼠的AXL抑制增加了产生IFN-β的巨噬细胞和树突状细胞的数量,并且抑制了嗜中性粒细胞的浸润(Shibata 2014)。AXL-null小鼠对ZIKA发病机制具有抗性,可能是由于病毒进入减少和IFN响应增强的组合(Hastings 2019),这表明AXL抑制剂在病毒感染期间作为治疗剂的潜在作用。
随着AXL被若干种不同的包膜病毒(例如,埃博拉、寨卡))靶向以进入细胞,并且抑制病毒免疫响应,AXL已经被公认为用于治疗包括SARS-CoV-2的多种的包膜病毒的感染的良好药物靶标。BMS-777607(一种用于AXL的抑制剂)在培养的细胞测定中强烈地抑制AXL和MER的配体依赖性激活,在30-3600nM的范围内的浓度下有效地阻断Gas6触发的受体激活。用BMS-777607处理的野生型骨髓来源的树突状细胞比未处理的细胞对病毒感染更不敏感(Bhattacharyya 2013)。已经证明另一种AXL抑制剂BGB324(贝森替尼(bemcentinib))在动物模型中对致死性埃博拉病毒感染具有效果(Dowall,2016)。在初步的体外研究中,贝森替尼显示出保护细胞免受SARS-CoV-2诱导的细胞病变效应。随后的研究验证了贝森替尼有效地抑制细胞的SARS-CoV-2感染的能力,支持了AXL抑制剂用于治疗早期SARS-CoV-2感染的潜在用途,并且将其选择作为在英国对住院COVID-19患者进行的多中心II期临床试验中快速跟踪的首个候选药物。(BerGenBio,2020年4月28日新闻稿)。
如在“AXL促进肺和支气管上皮细胞的SARS-CoV-2感染”(Wang 2020)中所公开的,发现酪氨酸蛋白激酶受体AXL与宿主细胞膜上的SARS-CoV-2S蛋白特异性地相互作用。当在不高度表达AXL或ACE2的细胞中过表达时,AXL与ACE2一样有效地促进病毒进入。引人注目的是,删除AXL,而不是ACE2,显著降低了SARS-CoV-2病毒假型对肺细胞的感染。可溶性人重组AXL,而不是ACE2,阻断肺细胞中的SARS-CoV-2病毒假型感染。综上所述,他们的发现表明AXL可能在促进人类呼吸***的SARS-CoV-2感染中起重要作用,并且是未来临床干预策略的潜在目标。
为了进一步支持使用AXL抑制剂作为抗病毒药剂的作用,一项研究探索了SARS-CoV-2感染的全球磷酸化前景(Bouhaddou 2020)。SARS-CoV-2-感染的Vero E6细胞的磷酸化蛋白质组分析揭示了宿主细胞途径被病毒感染劫持。SARS-CoV-2感染促进了酪蛋白激酶II(CK2)和p39MAPK激活,产生多种细胞因子,并且关闭有丝***激酶,导致细胞周期停滞。在一项对68种药物和化合物的筛选研究中,发现对p38、CK2、CDK、AXL和PIKFYVE激酶的药理学抑制具有抗病毒活性,代表了潜在的COVID-19疗法。对于AXL抑制剂吉瑞替尼(gilteritinib)观察到有效的抗病毒活性(IC50=0.807uM)。作者指出,已知AXL调节各种细胞内途径,包括Ras/ERK、PI3K和p38。在SARS-CoV-2感染期间,p38的抑制抑制了细胞因子的产生,并且损害了病毒复制,这表明对AXL的抑制,以及随后对p38信号转导的抑制,可能针对与COVID-19发病机制相关的多种机制。
已经发现用SARS-CoV-2感染肺癌细胞诱导与上皮细胞向***转化(EMT)一致的代谢和转录变化,包括上调ZEB1和AXL,从而在感染后下调ACE2(Stewart 2020)。研究人员发现,用AXL抑制剂贝森替尼治疗下调了ZEB1。基于他们的发现,他们得出结论,AXL抑制剂可以作为一种疗法,使SARS-CoV-2感染的细胞远离间质表型移动。
另一个最近的出版物表明,AXL是促进肺和支气管上皮细胞的感染的SARS-CoV-2的候选受体(Wang 2021)。发现酪氨酸蛋白激酶受体AXL与SARS-CoV-2S的N端结构域特异性地相互作用。在SARS-CoV-2病毒假型和真性SARS-CoV-2中,HEK293T细胞中AXL的过表达被证明与ACE2的过表达一样有效地促进SARS-CoV-2的进入,而敲除AXL显示显著地减少H1299肺细胞和人类原代肺上皮细胞中的SARS-CoV-2感染。可溶性人重组AXL阻断表达高水平AXL的细胞中的SARS-CoV-2感染。在来自COVID-19患者的支气管肺泡灌洗液细胞中,AXL表达水平与SARS-CoV-2S水平密切相关。
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发明内容
本文提供了使用有效且选择性的AXL抑制剂的抗病毒疗法。特别地,AXL抑制剂可以用于预防或治疗肺和支气管上皮细胞的感染。重要的是,因为AXL在病毒进入以及调节细胞因子产生、病毒复制和EMT中起作用,所以本文所述的AXL抑制剂能够通过降低病毒复制和抑制病毒进入来进行早期疾病干预,从而预先阻止严重呼吸道症状或其他器官代偿失调的潜在发展。
具体地,充当抗病毒药剂的AXL抑制剂是3-(5-(环丙基甲基)-1,3,4-噁二唑-2-基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-2-胺(“SLC-391”)。
在各种实施例中,病毒感染由呼吸道病原体引起,呼吸道病原体如冠状病毒,包括感染人类和非人类动物的那些病毒,如β冠状病毒(例如,SARS和MERS)。
在各种实施例中,将抗病毒药剂(SLC-391)施用于对病毒感染有症状的患者。在其他实施例中,将抗病毒药剂(SLC-391)施用于对病毒感染测试呈阳性的无症状患者。
在其他实施例中,抗病毒药剂(SLC-391)与第二抗感染药剂(例如干扰素、利巴韦林(ribivarin)等)共同施用。
附图说明
图1示出了SLC-391对Vero E6细胞的SARS-CoV-2感染的抑制作用。
图2示出了SLC-391在基于慢病毒的SARS-CoV-2假病毒中和测定中的中和曲线。
图3证明了如通过细胞病变效应(CPE)评估的针对人类流感病毒的抗病毒作用。
具体实施方式
本公开的各种实施例涉及TAM家族激酶抑制剂(例如,AXL抑制剂)作为抗感染药剂用于预防或治疗感染性疾病的用途,感染性疾病包括肺和支气管上皮细胞的感染。特别地,AXL抑制剂(SLC-391)对由冠状病毒(如SARS-CoV-1、SARS-CoV-2和MERS-CoV)引起的严重急性呼吸综合征(SARS)有效。
AXL抑制剂SLC-391
选择性AXL抑制为治疗由病毒病原体引起的疾病提供了可行的疗法。本公开的AXL抑制剂(SLC-391)具有以下化学结构:
SLC-391是一种选择性和有效的小分子AXL抑制剂,潜在的第一类具有期望的效力和药学性质。SLC-391是一种IC50在纳摩尔(nM)范围内的口服AXL激酶抑制剂,其已经在血液和实体瘤中证明了体外和体内活性。SLC-391及其药学上可接受的形式(例如,盐、溶剂化物、水合物或前药)在WO 2015/081257中更详细地描述,该文献通过引用以其整体并入本文。
SLC-391目前正在对在口服给药患有实体瘤的受试者之后的安全性和药代动力学的I期、开放标签、剂量递增和剂量扩展研究进行评估(SLC-391-101)。支持I期试验的非临床和安全药理学研究,以及获得已知在具有良好暴露的人类受试者中良好耐受的临床药物,使得SLC-391唯一能够进入临床评估抗病毒治疗剂,并且被研究为住院COVLD-19患者的潜在治疗方法。
A.体外药理学
SLC-391是一种有效且特异性的AXL抑制剂(对AXL的IC50为9.6nM,相对于对TYRO3为42.3nM,并且对MER为63.5nM)。与其他酪氨酸激酶相比,SLC-391也证明对TAM激酶的良好选择性。在体外BaF3细胞测定中,针对一组93种受体酪氨酸激酶筛选SLC-391,并且结果显示100nM的SLC-391仅以>60%抑制4种受体酪氨酸激酶(AXL[69%]、MER[61%]、VEGFR1[64%]、FGFR3[64%])。使用放射性磷酸转移酶测定,针对来自人类激酶组的一组320种蛋白激酶,进一步评估了SLC-391的选择性。结果表明SLC-391的良好的选择性概况,并且以下激酶被抑制的程度与AXL相似(IC50值):c-MET(12nM)、RET(28nM)、ROS1(23nM)、EPHA6(45nM)、ALK1(31nM)、NUAK1(62nM)和Aurora C(51nM)。此外,在人类NSCLC细胞系A549中,SLC-391抑制Gas6诱导的Akt磷酸化(指示AXL活性)的IC50为0.29μM。
SLC-391已经显示在多种来源的细胞系中显示出抗增殖活性,在这些细胞系中AXL被大量表达,包括肺、乳腺和造血谱系。细胞增殖活性的IC50值在1.05μM(4T1)至3.45μM(K562)的范围内。SLC-391还证明了锚定非依赖性细胞增殖的浓度依赖性损伤,其中在A549细胞中在1μM时观察到完全抑制。尽管在A549中仅观察到对细胞迁移的适度影响(在1μM时少于40%的减少),但SLC-391在远低于用于抗增殖的IC50值的浓度下阻止细胞侵袭;0.2μM的SLC-391抑制A549细胞侵袭约75%。
B.体内药理学
SLC-391的重要体内药理学研究已经完成,以支持其肿瘤学适应症。研究了SLC-391在口服给药(PO)(每日两次[BID]和每日一次[QD])时的体内生物利用度。SLC 391的生物有效剂量被认为在50至75mg/kg BID之间,其中肿瘤生长抑制率(TGI)分别在60%至67%的范围内。口服给药SLC-391还导致肿瘤异种移植物样品中磷酸化的Akt的水平降低41%。
C.安全性药理学
对于SLC-391已经完成了安全性药理学、非临床药代动力学(PK)和代谢研究,以支持当前的1期临床计划。在标准hERG测定中,SLC-391在测试的浓度下没有表现出hERG抑制作用,其中半最大抑制浓度(IC50)被确定为大于30μM。参考标准多非利特(dofetilide)的IC50为20nM,其在文献报道的范围内。
在对比格犬(雄性和雌性)的28天的口服灌胃毒理学研究中,SLC-391对P-QRS-T复合物的形态以及PR间期、QT间期和QTc间期或QRS复合物持续时间的定量测量没有可观察到的影响。对心率(HR)没有影响,并且对呼吸参数没有SLC-391相关的影响。在一项对Sprague-Dawley大鼠(雄性和雌性)的28天的口服灌胃毒理学研究中,基于功能观察组评估,不存在SLC-391相关的不良中枢神经***(CNS)影响。
为了确定SLC-391的生物利用度,在3个物种(CD-1小鼠、Sprague-Dawley大鼠和比格犬)中使用PO给药和IV给药进行了单剂量PK研究。此外,作为良好实验室规范(GLP)在大鼠和犬中的28天的口服毒理学研究的一部分,在单次和重复口服给药之后对TK进行评估。
在遗传毒性筛选研究中,SLC-391在有和没有肝脏S9代谢激活的情况下在沙门氏菌测试菌株TA98和TA100(Ames筛选测试)中呈阴性。在Flowscreen测定中,SLC-391被归类为具有非整倍体作用机制的潜在遗传毒性,并且在70mg/kg/天的最高剂量下而不是在13mg/kg/天下在体内大鼠微核测定中观察到潜在的遗传毒性响应。
对于SLC-391,已经完成了所有非临床毒理学研究,以支持当前的I期临床计划。这些研究包括大鼠和犬的单剂量最大耐受剂量(MTD)、大鼠和犬的非GLP重复剂量研究以及大鼠和犬的28天GLP研究。在28天的大鼠GLP毒理学研究中,NOAEL为30mg/kg/天。70mg/kg/天的剂量水平(测试的最高剂量)被定义为用于计算起始临床剂量的严重毒性剂量,其中人体当量剂量(HED)等于11.3mg/kg。在28天的犬GLP毒理学研究中,6mg/kg/天是如在ICH S9中定义的HNSTD,其中,HED等于3.3mg/kg。由于犬的HED(3.3mg/kg)低于大鼠的HED(11.3mg/kg),因此犬似乎比大鼠对SLC-391的毒性更敏感。如在PK研究中观察到的,与大鼠相比,这种增加的敏感性可能与犬的较高的口服生物利用度有关。
SLC-391的治疗用途
各种实施例提供了SLC-391或其任何一种药学上可接受的形式(例如,盐、溶剂化物、水合物或前药)作为抗病毒药剂在受试者中抗感染或治疗由感染引起的疾病的治疗用途。术语“受试者”和“患者”在本文中可互换使用,并且是指动物,包括但不限于人类和非人灵长类动物,包括猿猴和人类;啮齿动物,包括大鼠和小鼠;牛;马;绵羊;猫科动物;犬科动物等。“哺乳动物”是指任何哺乳动物物种的一个或多个成员,例如包括犬科动物;猫科动物;马;牛;绵羊;啮齿目动物以及灵长类动物,例如非人灵长类动物和人类。非人动物模型,例如哺乳动物,例如非人灵长类、鼠科动物、兔形目等,可以用于实验研究。
一个具体实施例提供了用于在受试者中预防或治疗疾病或感染的式(I)的化合物(即SLC-391)。在更具体的实施例中,感染由冠状病毒或流感病毒引起。
在一些实施例中,感染或疾病由冠状病毒引起。在更具体的实施例中,冠状病毒是SARS冠状病毒(SARS-CoV)和/或SARS-CoV-2。在甚至更具体的实施例中,疾病是由2019新型冠状病毒SARS-CoV-2引起的COVID-19。
在一些实施例中,由冠状病毒引起的疾病是呼吸道疾病,其可以包括肺炎(轻度和重度)、急性呼吸道感染、严重急性呼吸道感染(SARI)、缺氧性呼吸衰竭、急性呼吸窘迫综合征、败血症、脓毒性休克或严重急性呼吸综合征(SARS)。
呼吸道疾病的症状可以包括来自简单感染的轻微症状,如发烧、咳嗽、喉咙痛、鼻塞、疲劳、头痛和肌肉疼痛。更严重的感染(例如肺炎、SARI)的症状可以包括呼吸频率增加、严重呼吸衰竭或呼吸困难、中心性发绀、嗜睡、意识不清或痉挛、喘息等。老年人和免疫抑制的人可能具有不典型的症状。
在某些实施例中,将抗感染药剂(SLC-391)施用于对冠状病毒测试阳性而未表现出症状的无症状受试者。
在其他实施例中,抗感染药剂(SLC-391)在对冠状病毒测试阳性的0-7天内、或0-5天内、或0-3天内、或0-1天内被施用于受试者。
“测试阳性”意指对来自特定病毒的遗传材料或特定病毒的表面上的蛋白质或蛋白质片段的明确检测。
另一实施例提供了一种式(I)的化合物(SLC-391),其用于抑制或减少病毒在受试者的哺乳动物细胞中复制或繁殖。特别地,细胞是肺和支气管上皮细胞。在更具体的实施例中,病毒是冠状病毒,并且式(I)的化合物降低细胞中冠状病毒的核酸负载。
另外的实施例提供了一种式(I)的化合物(SLC-391),其用于阻断SARS-CoV-2刺突蛋白与其宿主受体ACE2结合。
在其他实施例中,抗病毒药剂(SLC-391)与第二抗感染药剂(例如,干扰素、利巴韦林、利托那韦、单克隆抗体等)共同施用。
在优选的实施例中,式(I)的化合物(SLC-391)经口服给药。在其他实施例中,式(I)的化合物(SLC-391)通过腹膜内或静脉内给药被施用。
实例1
基于抗病毒细胞的测定
使用qPCR方法进行了有效的基于细胞的测定,以测试SLC-391对Vero E6细胞的SARS-CoV-2感染的抑制。图1总结了结果,其证明SLC-391能够抑制Vero E6细胞的SARS-CoV-2感染,如通过复制病毒RNA所需的循环所测量的(循环次数越多,感染越低)。如所示出的,在1μM的浓度下,在长达72小时,达到了高度病毒抑制。即使在0.01μM的浓度下,SLC-391也可以有效地抑制病毒感染持续24小时。图1进一步证明了对病毒复制的剂量依赖性抑制。
实例2
在假病毒中和测定中,SLC-391抑制SARS-COV-2刺突蛋白与ACE2的结合
方法:通过使用GenScript假病毒中和测定来测量SLC391用于阻断SARS-CoV-2刺突蛋白与其宿主受体ACE2结合的抑制活性。SLC391用Opti-MEM以一式两份连续稀释,在测定板中与假病毒混合,并且在室温下温育1小时。将人ACE2过表达的CHO细胞(CHO-hACE2细胞)在DMEM完全生长培养基中稀释至6×106个细胞/mL的浓度,并且加入到SLC-391-假病毒混合物中。在37℃和5% CO2下温育34小时之后,加入新鲜的DMEM完全生长培养基,并且再温育24小时。小心地除去生长培养基。在除去培养基之后立即加入新制备的荧光素酶检测试剂,并且切在室温下温育15分钟。测量荧光素酶活性(在相对光(RLU)下)。将未感染的细胞视为100%中和并且将单独感染假病毒的细胞视为0%中和,将中和百分比归一化。
结果:SLC391SARS-CoV-2中和测定是一种基于慢病毒的假病毒中和测定,用于检测SLC-391在中和SARS-CoV-2刺突蛋白中的效力。本测定中描述的刺突蛋白位于基于慢病毒的假病毒颗粒的表面,因此假病毒可以与由CHO-hACE2细胞过表达的ACE2结合,模拟冠状病毒-细胞膜的融合过程。在感染之后,假病毒可以在细胞中表达携带的荧光素酶基因。通过测量荧光素酶活性,可以推断假病毒感染的程度。在测试的中和测定中,SLC-391显著降低了生物发光信号(图2)。这证明SLC-391能够阻断ACE2和刺突蛋白的相互作用,并且以剂量依赖性方式防止假病毒感染。在1μM的浓度下,SLC-391能够完全中和与CHO-hACE2细胞结合的SARS-CoV-2假病毒,并且防止其感染。
实例3
SLC-391对人流感A诱导的细胞病变效应提供细胞保护
方法:通过化学发光终点(CellTiterGlo)测量在RPMI2650细胞中复制人类流感病毒(FluAPR834)后病毒诱导的细胞病变效应(CPE)的抑制和细胞活力。将细胞(5×105个细胞/孔)接种在96孔平底组织培养板中,并且允许在37℃和5% CO2下粘附过夜。在温育之后,将稀释的测试化合物和稀释至预定滴度以在感染后4天产生至少50%细胞杀伤的病毒(流感A)加入到板中。在37℃、5% CO2下温育4天后,使用CellTiterGlo测量细胞活力。使用四参数曲线拟合分析,计算病毒感染的孔的减少百分比和未感染的化合物对照孔的细胞存活百分比,以确定EC50和TC50值。EC50是以50%抑制CPE的测试化合物的浓度;TC50是在没有病毒的情况下导致50%细胞死亡的测试化合物的浓度。治疗指数(TI)被计算为TC50除以EC50。
结果:SLC-391显示了在RPMI2650细胞中对人流感A诱导的细胞病变效应(CPE)的细胞保护作用。EC50和TC50分别为0.14μM和>10μM。治疗指数(TI)达到71.4以上。
如图3所示,评价了SLC-391对RPMI2650细胞中人类流感病毒(流感A)感染的细胞保护作用。在存在或不存在各种浓度的SLC-391的情况下,在37℃、5% CO2下,用流感A处理细胞4天。在没有病毒感染的情况下评估SLC-391诱导的细胞毒性。通过CellTiterGlo确定细胞活力。相对于没有用SLC-391处理的细胞确定病毒CPE减少的百分比和细胞对照的百分比。
实例4
SLC391证明了在感染流感A的RPMI2650细胞中病毒产量减少
方法:将RPMI2650细胞以5000个细胞/孔接种,并且温育过夜以用于粘附到96孔微量滴定板上。在过夜温育后,除去细胞培养基,并且用PBS洗涤细胞单层一次。将一百(100)μL/孔的测定培养基加入到板中。收集来自流感A细胞保护测定(感染后第4天)的测试浓度为10μM、0.2μM和0.003μM的上清液样品,并且将每个处理浓度合并。将三份病毒对照上清液合并。样品在测定培养基中以对数增量连续稀释,并以100μL/孔以一式四份加入到细胞中。在37℃、5% CO2下温育4天后,计算用CellTiterGlo染色的细胞活力和TCID50/mL。通过与未处理的病毒比较来确定SLC-391处理的病毒的病毒感染性变化倍数。
表1:SLC-391对流感病毒(流感A)产量减少测定的影响
结果:SLC-391证明了在感染流感A的RPMI2650细胞中病毒产量减少。当SLC-391在10μM、0.4μM和0.003μM测试浓度时,当与病毒对照比较时,病毒减少的倍数分别达到952.9、74.9和34.8。
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本说明书中引用的和/或在申请数据表中列出的所有美国专利、美国专利申请出版物、美国专利申请、外国专利、外国专利申请和非专利出版物,包括2021年2月1日提交的美国专利申请第63/144,453号,通过引用以其整体并入本文。
从上文可以理解,尽管为了说明的目的已经在本文中描述了本公开的具体实施例,但是在不脱离本公开的精神和范围的情况下,可以进行各种修改。因此,除了所附权利要求之外,本公开不受限制。
Claims (15)
1.一种式(I)的化合物,其用途在于预防或治疗感染或由感染引起的疾病,其中所述化合物具有以下结构:
2.根据权利要求1所述的化合物,其中所述用途包括预防或治疗由冠状病毒或流感病毒引起的感染。
3.根据权利要求1或权利要求2所述的化合物,其中所述冠状病毒是SARS-CoV或SARS-CoV-2。
4.根据权利要求1至3中任一项所述的化合物,其中由感染引起的所述疾病是呼吸***疾病。
5.根据权利要求1至4中任一项所述的化合物,其中所述疾病是COVID 19。
6.根据权利要求2至5中任一项所述的化合物,其中所述用途包括将式(I)的所述化合物施用于对所述病毒测试阳性的无症状受试者。
7.根据权利要求2至5中任一项所述的化合物,其中所述用途包括在对所述病毒测试阳性的0-7天内向受试者施用式(I)的所述化合物。
8.一种式(I)的化合物,其用途在于抑制或减少受试者的细胞中病毒的复制或繁殖,其中所述化合物具有以下结构:
9.根据权利要求8所述的化合物,其中所述细胞是肺和支气管上皮细胞。
10.根据权利要求8或权利要求9所述的化合物,其中所述病毒是冠状病毒或流感病毒。
11.根据权利要求8至10中任一项所述的化合物,其中所述冠状病毒是SARS-CoV或SARS-CoV-2。
12.根据权利要求8至11中任一项所述的化合物,其中所述用途包括将式(I)的所述化合物施用于对所述病毒检测阳性的无症状受试者。
13.根据权利要求8至11中任一项所述的化合物,其中所述用途包括在对病毒测试阳性的0-7天内向受试者施用式(I)的所述化合物。
14.一种式(I)的化合物,其用途在于阻断SARS-CoV-2刺突蛋白与其宿主受体ACE2结合,其中所述化合物具有以下结构:
15.根据权利要求14所述的化合物,其中所述用途包括治疗COVID 19。
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JP (1) | JP2024505089A (zh) |
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EP4284368A1 (en) | 2023-12-06 |
JP2024505089A (ja) | 2024-02-02 |
WO2022165436A1 (en) | 2022-08-04 |
TW202245764A (zh) | 2022-12-01 |
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