CN116889562A - 与神经退行性疾病相关的神经炎症中的巨噬细胞/小胶质细胞 - Google Patents
与神经退行性疾病相关的神经炎症中的巨噬细胞/小胶质细胞 Download PDFInfo
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Abstract
本文描述了治疗神经元炎症病症,例如阿尔茨海默病、帕金森氏病、亨廷顿病、缺血性中风和朊病毒病的方法,包括给予治疗有效量的色甘酸或色甘酸衍生化合物。
Description
相关申请
本申请要求2016年8月31日提交的美国临时专利申请序列号62/382,192的优先权,该临时专利申请通过引用整体并入本文。
技术领域
本发明涉及治疗神经元炎症病症的方法,包括给予需要的患者治疗有效量的至少一种具有下式的化合物:
背景
已经研究了调节单核细胞和小胶质细胞活性的策略,尤其是那些可以防止小胶质细胞介导的神经毒性的策略。(参见Zhao等人,“抗炎细胞因子,白细胞介素-4,对活化小胶质细胞诱导的运动神经元毒性的保护作用(Protective effects of an anti-inflammatory cytokine,interleukin-4,on motoneuron toxicity induced byactivated microglia)”,J.Neurochem.2006,99:1176–1187;Heneka等人,“在阿尔茨海默病中被激活并导致APP/PS1小鼠的病理学的NLRP3(NLRP3 is activated in Alzheimer'sdisease and contributes to pathology in APP/PS1 mice)”,Nature,2013,493(7434):674-8;Theeriault等人,“阿尔茨海默病中单核细胞和小胶质细胞的动力学(The dynamicsof monocytes and microglia in Alzheimer’s disease)”,Alzheimers Res Ther.,2015,7:41;Nau等人,“提高小胶质细胞活性作为大脑抵抗感染的有效保护剂的策略(Strategies to increase the activity of microglia as efficient protectors ofthe brain against infections)”,Front Cell Neurosci.,2014,8:138。)总体来说,很明显需要更多的重点研究以更好地确定每种炎症状态如何调节神经退行性疾病如阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS)的病理学。单核细胞和小胶质细胞的早期活化有可能通过调节免疫应答从而增加单核细胞和小胶质细胞的内在吞噬能力来减缓神经变性进展,而不会引起可能恶化神经变性的促炎细胞因子的分泌。
大脑中淀粉样蛋白斑块和神经原纤维缠结的存在下神经炎症反应的作用及其在AD病理学中的相关神经元损失已经很好地建立并且被广泛研究。参见Walker等人,“人神经退行性疾病中小胶质细胞的免疫表型:检测人脑中小胶质细胞极化的挑战(Immunephenotypes of microglia in human neurodegenerative disease:challenges todetecting microglial polarization in human brains)”,Alzheimers Res Ther.,2015,7:56;Theerialut等人,2015;Wilcock,DM,“阿尔茨海默病中神经炎症的作用的变化观点(A Changing Perspective on the Role of Neuroinflammation in Alzheimer’sDisease)”,International Journal of Alzheimer’s Disease,2012,文章编号495243;McGeer等人,“针对小胶质细胞治疗阿尔茨海默病(Targeting microglia for thetreatment of Alzheimer's disease)”,Expert Opin Ther Targets,2015,19(4):497-506)。大量研究表明,小胶质细胞介导的炎症有助于AD的进展,并且发现小胶质细胞与淀粉样蛋白β(Aβ)沉积物密切相关。(参见Mandrekar等人,“阿尔茨海默病的小胶质细胞和炎症(Microglia and Inflammation in Alzheimer’s Disease)”,CNS Neurol Disord DrugTargets,2010,9(2):156–167)。
众所周知,小胶质细胞(脑驻留巨噬细胞)的性质变化取决于它们对其微环境中不同刺激物(例如细胞因子)的响应,导致一系列表型。基于细胞因子、受体和其他标志物表达的变化,单核细胞和巨噬细胞状态被定义为:经典激活(M1),替代激活(M2a),II型替代激活(M2b)和获得性失活(M2c)。(参见Walker等人,2015;Martinez等人,“巨噬细胞的替代激活:免疫功能观点(Alternative activation of macrophages:an immunologic functionalperspective)”,Annu Rev Immunol.2009,27:451-83;Mantovani等人,“趋化因子系统以多种形式的巨噬细胞激活和极化(The chemokine system in diverse forms ofmacrophage activation and polarization)”,Trends Immunol.,2004,25:677–686;Sternberg,EM.,“先天免疫的神经调节:对病原体的协调的非特异性宿主响应(Neuralregulation of innate immunity:a coordinated nonspecific host response topathogens)”,Nat Rev Immunol.,2006,6(4):318-28)。最近,许多研究试图阐明这些表型在AD脑中的作用,并确定这些细胞促成AD相关神经炎症的机制。(参见Mandrekar等人,2012;McGeer等人,2015;和Wilcock,2012)。
小胶质细胞与纤维状Aβ的相互作用导致其表型活化,并且最近已被认为在神经保护中起作用。(参见Zhao等人,2006;Figueiredo等人,“神经元-小胶质细胞串扰上调神经元FGF-2表达,通过JNK1/2介导对兴奋性毒性的神经保护作用(Neuron-microglia crosstalkup-regulates neuronal FGF-2expression which mediates neuroprotection againstexcitotoxicity via JNK1/2)”,J.Neurochem.,2008Oct.,107(1):73-85)。许多研究表明,在小鼠和人类中,神经胶质细胞通过改变其形态特征,表达大量细胞表面受体和周围病变来应对AD病理损伤(斑块和缠结)的存在。(参见Perlmutter等人,“小胶质细胞与阿兹海默病老年斑淀粉样蛋白的形态学关联(Morphologic association between microglia andsenile plaque amyloid in Alzheimer’s disease)”,Neurosci Lett.,1990,119:1,32–36;Combs等人,“鉴定小胶质细胞信号转导途径介导对β-淀粉样蛋白和朊蛋白的淀粉样蛋白形成片段的神经毒性反应(Identification of microglial signal transductionpathways mediating a neurotoxic response to amyloidogenic fragments ofβ-amyloid and prion proteins)”,J.Neurosci.,1999,19:3,928–939)。另一方面,响应于AD脑中的细胞碎片的巨噬细胞和小胶质细胞激活以及随后的促炎细胞因子的释放导致加速的神经变性。反过来,这会产生更多细胞碎片并加速疾病进展。(参见Rubio-Perez等人,“综述:阿尔茨海默病的炎症过程,细胞因子的作用(A Review:Inflammatory Process inAlzheimer's Disease,Role of Cytokines)”,Scientific World Journal,2012,756357;McGeer等人,“炎症机制在阿尔茨海默病中的重要性(The importance of inflammatorymechanisms in Alzheimer disease)”,Exp.Gerontol.1998,33:5,371–378;Akiyama等人,“炎症和阿尔茨海默病(Inflammation and Alzheimer's disease)”,Neurobiol Aging,2000,21(3),383-421;Liu等人,“TLR2是阿尔茨海默氏病淀粉样蛋白β肽的主要受体,可引发神经炎症激活(TLR2 is a primary receptor for Alzheimer's amyloidβpeptide totrigger neuroinflammatory activation)”,J.Immunol.2012,188(3):1098-107)。
一些研究集中于小胶质细胞激活及其在AD病变清除中的作用,导致脑中淀粉样蛋白沉积物的减少。(参见DiCarlo等人,“海马内LPS注射减少APP+PS1转基因小鼠中的Aβ负荷(Intrahippocampal LPS injections reduce Aβload in APP+PS1 transgenic mice)”,Neurobiol of Aging,2001,22:6,1007–1012;Herber等人,“在APP转基因小鼠中施用颅内LPS后Aβ水平的时间依赖性降低(Time-dependent reduction in Aβlevels afterintracranial LPS administration in APP transgenic mice)”,Exp.Neurol.,2004,190(1):245-53;Liu等人,2012)。虽然围绕Aβ斑块的常驻小胶质细胞在降解Aβ方面不如新渗入的巨噬细胞或单核细胞有效,(参见Thériault等人,2015;Varnum等人,“小胶质细胞激活表型分类对阿尔茨海默氏症中神经退行性变和再生的影响(The classification ofmicroglial activation phenotypes on neurodegeneration and regeneration inAlzheimer's disease brain)”,Arch.Immunol.Ther.Exp.(Warsz),2012,60(4):251-66),已经表明小胶质细胞确实能够内化纤维状和可溶性Aβ,但是无法处理这些肽。(参见Chung等人,“通过小胶质细胞摄取,降解和释放纤维状和可溶形式的阿尔茨海默氏淀粉样蛋白β-肽(Uptake,degradation,and release of fibrillar and soluble forms ofAlzheimer's amyloid beta-peptide by microglial cells)”,J.Biol.Chem.,1999,274:32301–8)。
此外,已经假定小胶质细胞在衰老期间经历从M2-转变为M1-倾斜激活表型。(参见Heneka等人,2013;Varnum等人,2012;Gratchev等人,“Mphi1和Mphi2可分别被Th2或Th1细胞因子重新极化,并对外源性危险信号做出响应(Mphi1 and Mphi2 can be re-polarizedby Th2 or Th1 cytokines,respectively,and respond to exogenous dangersignals)”,Immunobiology,2006,211(6–8):473–486;Colton等人,“AD中和AD小鼠模型中巨噬细胞替代激活基因的表达谱(Expression profiles for macrophage alternativeactivation genes in AD and in mouse models of AD)”,J.Neuroinflammation,2006,3:27)。然而,大脑中的免疫应答如何在AD中被驱动仍然是一个争论的问题,特别是神经炎症是否可以由年龄相关的全身性炎症引发。(参见Thériault等人,2015)。已经表明小胶质细胞的刺激可以增强其内在的吞噬能力,更有效地降解Aβ;已经提出了许多调节小胶质细胞响应的策略。(参见Mandrekar,2010;Kiyota等人,“CNS表达抗炎细胞因子白细胞介素-4减弱APP+PS1生物小鼠的阿尔茨海默病样发病机制(CNS expression of anti-inflammatory cytokine interleukin-4attenuates Alzheimer’s disease-likepathogenesis in APP+PS1 bigenic mice)”,FASEB J.2010,24:3093–3102;He等人,“肿瘤坏死因子死亡受体的缺失抑制淀粉样蛋白β的产生,并预防阿尔茨海默氏症小鼠的学习和记忆缺陷(Deletion of tumor necrosis factor death receptor inhibits amyloidbeta generation and prevents learning and memory deficits in Alzheimer’smice)”,J.Cell Biol.,2007,178:829–841;Varnum等人,2012)。
已经显示小胶质细胞被细胞外沉积的Aβ肽激活(Lotz等人,“在原代小鼠小胶质细胞培养物中淀粉样蛋白β肽1-40增强Toll样受体-2和-4激动剂的作用但拮抗Toll样受体-9-诱导的炎症(Amyloid beta peptide 1-40enhances the action of Toll-likereceptor-2and-4agonists but antagonizes Toll-like receptor-9-inducedinflammation in primary mouse microglial cell cultures)”,J.Neurochem.,2005,94:289–298;Reed-Geaghan等人,“CD14和toll样受体2和4是纤维状Aβ刺激的小胶质细胞激活所必需的(CD14 and toll-like receptors 2and 4are required for fibrillar Aβ-stimulated microglial activation)”,J.Neurosci.,2009,29:11982–11992)。这类似于响应干扰素-γ(IFNγ),来自T细胞的肿瘤坏死因子α(TNFα)或抗原呈递细胞的存在的小胶质细胞活化。M1激活的小胶质细胞可以产生活性氧物质并导致促炎细胞因子如TNFα和白细胞介素(IL)-1β的产生增加。
小胶质细胞的M1型响应已被证明可降低淀粉样蛋白负荷,但会加剧神经原纤维缠结病理。Shaftel等人(Shaftel等人,“持续海马IL-1β过度表达介导慢性神经炎症和改善阿尔茨海默病斑块病理学(Sustained hippocampal IL-1βoverexpression mediateschronic neuroinflammation and ameliorates Alzheimer plaque pathology)”,J.Clin.Invest.,2007,117(6):1595-604)已显示IL-1β表达可能是在AD中有益的神经炎症反应的基础,并且APP/PS1转基因小鼠的海马中IL-1β过表达导致淀粉样蛋白负荷减少。作者提出,IL-1β介导的小胶质细胞活化是减少淀粉样蛋白沉积的机制。此外,Montgomery等人(Montgomery等人,“阿尔茨海默病小鼠中TNF-RI/RII表达的消除导致病理学的意外增强:对脑中慢性泛TNF-α抑制治疗策略的影响(Ablation of TNF-RI/RII expression inAlzheimer’s disease mice leads to an unexpected enhancement of pathology:implications for chronic pan-TNF-αsuppressive therapeutic strategies in thebrain)”,Am.J.Pathol.,2011,179(4):2053-70)已经表明,完整的TNF-受体信号传导对于小胶质细胞介导的细胞外淀粉样蛋白肽的摄取是至关重要的。虽然M1炎症表型似乎在许多研究中改善淀粉样蛋白病理学,但是在tau转基因小鼠或细胞培养物中诱导M1表型导致tau病理学的恶化。(参见Kitazawa等人,“脂多糖诱导的炎症通过阿尔茨海默氏病的转基因模型中的细胞周期蛋白依赖性激酶5-介导的途径加剧了tau病理学(Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase5-mediated pathway in a transgenic model of Alzheimer’s disease”),J.Neurosci.,2005,28;25(39):8843-53.;Li等人,“Interleukin-1通过p38-MAPK途径介导小胶质细胞对皮质神经元中tau磷酸化和突触素合成的病理学影响(Interleukin-1mediates pathological effects of microglia on tau phosphorylation and onsynaptophysin synthesis in cortical neurons through a p38-MAPK pathway)”,J.Neurosci.,2003,1;23(5):1605-11)。
巨噬细胞M2激活与已知有助于抗炎作用和细胞外基质的重组的介导物相关(Zhu等人,“哮喘Th2炎症和IL-13途径激活中的酸性哺乳动物几丁质酶(Acidic mammalianchitinase in asthmatic Th2 inflammation and IL-13pathway activation)”,Science,2004,304(5677):1678-82;Walker等人,2015;Wilcock等人,2012)。具有M2a表型的小胶质细胞具有增加的吞噬作用并产生生长因子,例如胰岛素样生长因子-1和抗炎细胞因子例如IL-10。IL-4和/或IL-13对巨噬细胞的刺激导致M2a状态,有时称为伤口愈合巨噬细胞(Edwards等人,“三种活化的巨噬细胞群的生物化学和功能表征(Biochemical andfunctional characterization of three activated macrophage populations)”,J.Leukoc Biol.,2006,80(6):1298-307),其通常表征为促炎细胞因子(IL-1,TNF和IL-6)的低产量。M2a响应主要在过敏反应、细胞外基质沉积和重塑中观察到。
M2b巨噬细胞的独特之处在于它们表达高水平的促炎细胞因子,这是M1活化的特征,但也表达高水平的抗炎细胞因子IL-10。(参见Moser DM.,“巨噬细胞活化的许多方面(The many faces of macrophage activation)”,J.Leukoc Biol.,2003,73(2):209-12)。
最后,M2c巨噬细胞状态被IL-10刺激,有时被称为调节性巨噬细胞。M2c巨噬细胞具有抗炎活性,其在细胞碎片的吞噬作用中起作用而没有经典的促炎反应(参见,MoserDM.,2003)。这些细胞表达TGFβ和高IL-10以及基质蛋白。(参见Mantovani等人,“多种形式的巨噬细胞活化和极化中的趋化因子系统(The chemokine system in diverse forms ofmacrophage activation and polarization)”,Trends Immunol.,2004,25:677–686;Wilcock等人,2012)。Plunkett等人(Plunkett等人,“白细胞介素-10(IL-10)对大鼠兴奋毒性脊髓损伤后疼痛行为和基因表达的影响(Effects of interleukin-10(IL-10)on painbehavior and gene expression following excitotoxic spinal cord injury in therat)”,Exp.Neurol.,2001;168:144–154)报道IL-10介导的抗炎反应包括减少胶质细胞活化和促炎细胞因子的产生。
然而,M2小胶质细胞激活的机制及其在AD和斑块病理学中的作用尚不清楚。(参见Mandrekar等人,2010)。此外,许多研究表明,响应疾病进展小胶质细胞激活状态发生转变(Colton等人,2006;Jimenez等人,“PS1M146L/APP751SL小鼠模型阿尔茨海默氏症的海马炎症反应:年龄依赖性小胶质细胞表型转换为经典(Inflammatory response in thehippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease:age-dependent switch in the microglial phenotype from alternative to classic)”,J.Neurosci.,2008,28:11650–11661)。在动物研究中已经报道,在疾病进展期间小胶质细胞活化表型从M2转变为M1(Jimenez等人,2008;Nolan等人,“白介素-4在调节年龄相关炎症变化中的作用(Role of interleukin-4in regulation of age-related inflammatorychanges in the hippocampus)”,J.Biol.Chem.,2005;280:9354–9362;Maher等人,“海马中IL-4诱导的信号传导的下调导致老年大鼠中LTP的缺陷(Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the agedrat)”,Neurobiol.Aging,2005,26:717–728),表明随着年龄的增加,替代表型的经典激活表型增加。一般认为,由细胞外沉积的Aβ激活的小胶质细胞通过触发抗炎/神经营养性M2激活和通过吞噬作用清除Aβ来保护神经元。这是新治疗目标的潜在途径。(参见He等人,2007;Yamamoto等人,“瑞典突变APP转基因小鼠中的干扰素-γ和肿瘤坏死因子-α调节淀粉样蛋白β斑块沉积和β-分泌酶表达(Interferon-gamma and tumor necrosis factor-alpharegulate amyloid-beta plaque deposition and beta-secretase expression inSwedish mutant APP transgenic mice)”,Am.J.Pathol.,2007,170:680–692;Yamamoto等人,“细胞因子介导的人单核吞噬细胞对纤维状淀粉样β肽降解的抑制(Cytokine-mediatedinhibition of fibrillar amyloid-beta peptide degradation by human mononuclearphagocytes)”,J.Immunol.,2008,181:3877–3886)。
Mantovani等人(Mantovani等人,2004)研究了IL-4作为M2a小胶质细胞激活的重要调节剂的作用。已经显示IL-4基因递送到APP+PS1小鼠中部分地抑制了海马中的胶质积聚,直接增强了神经发生,恢复了受损的空间学习,并且还减少了Aβ沉积(Kiyota等人,2010)。
Yamamoto等人(Yamamoto等人,2007,2008)在原代培养的人单核细胞衍生的巨噬细胞(MDM)和小胶质细胞中使用促炎细胞因子和抗炎细胞因子检测了巨噬细胞介导的Aβ降解。这些研究表明,抗炎和调节细胞因子导致M2a或M2c活化增加和Aβ清除增强。Kiyota等人(Kiyota等人,2011)已显示IL-4的持续表达减少了天花/小胶质细胞增生,淀粉样蛋白-β肽(Aβ)寡聚化和沉积,以及增强了神经发生。
已经提出了几种方法来调节小胶质细胞激活作为AD治疗的潜在靶标。(参见Thériault等人,2015;Cherry等人,“神经炎症和M2小胶质细胞:好的,坏的和发炎的(Neuroinflammation and M2 microglia:the good,the bad,and the inflamed)”,J.Neuroinflammation,2014,11:98;Mandrekar等人,2010;Vernum等人,2012)。已提出使用抗炎药物,如非甾体抗炎药(NSAID)来阻止AD的进展,可以抑制内源性分子的促炎和抗炎活化,从而消除M2小胶质细胞功能的有益作用和斑块清除的内源性机制。(参见Wilcock等人,2012,Cherry等人,2014;Theeriault等人,2015)。
研究主要集中在两个方面:抗炎剂,以缓和促炎细胞因子的毒性作用;以及将小胶质细胞从M1状态转变为M2状态,其中毒性作用降低并且其对Aβ的吞噬活性增强。已提出(McGreer等人,2012)应在疾病进展的早期进行潜在的治疗。
已经研究了调节单核细胞和小胶质细胞活性的策略,尤其是那些可以防止小胶质细胞介导的神经毒性的策略(Zhao等人,2006;Heneka等人,2013;Therlaut等人,2015;Nau等人,2014)。总体而言,显然需要进行更集中的研究以更好地确定每种炎症状态如何调节AD的病理。通常认为单核细胞和小胶质细胞的早期活化有可能通过调节免疫应答从而增加单核细胞和小胶质细胞的内在吞噬能力来减缓AD进展,而不会引起可能使AD恶化的促炎细胞因子的分泌。
发明内容
在一些实施方式中,本发明涉及治疗神经元炎症病症的方法,包括给予需要的患者治疗有效量的至少一种具有下式的化合物:
在其他实施方案中,该方法使用以下化合物:
色甘酸二钠;
F-色甘酸二酸;
ET-色甘酸;
F-ET-色甘酸;
三醇-色甘酸;
F-三醇-色甘酸;
Ac-三醇-色甘酸;
POM-色甘酸;或
在其他实施方案中,神经元炎症病症是ALS、AD、缺血性中风或朊病毒病中的至少一种。在一个实施方案中,化合物可以腹膜内(IP)和/或静脉内(IV)给药。化合物可以每天约1mg至约1000mg的剂量给药。给药方法可以是透皮给药或通过吸入给药。
在另一个实施方案中,该方法是治疗ALS的方法,其进一步包括共同给予CD4+;siRNA;改善ALS的miRNA;胶质形态调节剂;SOD1控制物;利鲁唑;或另一种控制神经炎症的M1;M2转化活性药物。
在某些实施方案中,本发明涉及本文所述的任何方法,条件是该化合物不是色甘酸二钠。在某些实施方案中,本发明涉及本文所述的任何方法,条件是当神经元炎症病症是AD时,该化合物不是色甘酸二钠,F-色甘酸二钠,ET-色甘酸或F-ET-色甘酸。
在某些实施方案中,本发明涉及以下化合物中的任何一种:
三醇-色甘酸;
F-三醇-色甘酸;
Ac-三醇-色甘酸;
POM-色甘酸;或
附图说明
图1A说明用PBS(磷酸缓冲盐溶液)或递增剂量的色甘酸钠处理一周后Aβx-40和Aβx-42的血浆水平的定量(n=3-5只小鼠/组)。
图1B示出了在用色甘酸钠(3.15mg/kg)或PBS每天处理持续7天的小鼠中淀粉样蛋白沉积物(6E10)和小胶质细胞(Iba1)的定位的代表性图像。条形图说明了分析每只动物斑块的结果。比例尺=10μm。
图1C说明了色甘酸钠对小胶质细胞体外Aβ摄取的影响,其中在孵育后,使用AβELISA测量培养基中Aβx-40(图1C左)Aβx-42(图1C,右)的浓度。
图2显示了实施例2研究的Tg-2576小鼠中围绕这些沉积物的斑块和小胶质细胞。该图显示了淀粉样蛋白沉积物和Iba-1阳性小胶质细胞的代表性图片。
图3显示用色甘酸处理的BV2小胶质细胞的结果,并且相对于用运载体处理的BV2小胶质细胞,色甘酸和布洛芬表现出增加的Aβ42摄取水平。
图4显示了使用本文所述的各种化合物的Aβ聚集抑制测定的结果。
图5图示说明色甘酸显著影响脑TBS可溶性Aβ的水平和Aβ(42:40)的比率。
图6A显示用DMSO(对照)处理16小时的幼稚BV2小胶质细胞。然后,将细胞与荧光标记的Aβ42和DMSO或色甘酸钠一起孵育2小时。孵育后,用质膜染料(PM)标记细胞并成像。
图6B显示用DMSO(对照)处理16小时的幼稚BV2小胶质细胞。然后,将细胞与荧光标记的Aβ42和DMSO或色甘酸钠一起孵育2小时。
图6C显示用色甘酸钠(500μM)处理16小时的幼稚BV2小胶质细胞。然后,将细胞与荧光标记的Aβ42和DMSO或色甘酸钠一起孵育2小时。孵育后,用质膜染料(PM)标记细胞并成像。
图6D显示用色甘酸钠(500μM)处理16小时的幼稚BV2小胶质细胞。然后,将细胞与荧光标记的Aβ42和DMSO或色甘酸钠一起孵育2小时。
图7A图示说明色甘酸钠促进小胶质细胞Aβ42摄取。用DMSO或不同浓度的色甘酸钠处理BV2小胶质细胞16小时。然后,将细胞与可溶性未标记的Aβ42和DMSO或色甘酸钠一起孵育2小时,并收集用于ELISA分析。与用运载体(DMSO)处理的细胞相比,用色甘酸钠处理的幼稚BV2和BV2-CD33WT小胶质细胞表现出增加的Aβ42摄取水平。
图7B图示说明色甘酸钠促进小胶质细胞Aβ42摄取。将稳定表达CD33(BV2-CD33WT)的BV2细胞用DMSO或不同浓度的色甘酸钠处理16小时。然后,将细胞与可溶性未标记的Aβ42和DMSO或色甘酸钠一起孵育2小时,并收集用于ELISA分析。与用运载体(DMSO)处理的细胞相比,用色甘酸钠处理的幼稚BV2和BV2-CD33WT小胶质细胞表现出增加的Aβ42摄取水平。
图8图示说明在LDH测定中以100μM或更高浓度测试时,化合物C8显示出毒性。将幼稚BV2小胶质细胞用DMSO或色甘酸衍生物以不同浓度处理3小时。在10,50,100和150μM下测试C1,C2,C5,C6,C7和C8,而由于DMSO中的溶解度限制,在5,25,50和75μM下评估C3和C4。然后,将细胞与可溶性未标记的Aβ42肽和DMSO或色甘酸衍生物一起f孵育2小时。在处理结束时,收集细胞培养基并用乳酸脱氢酶(LDH)测定评估化合物毒性。与用运载体(DMSO)处理的细胞相比,用色甘酸衍生物C8处理的BV2小胶质细胞在100和150μM时表现出增加的毒性。
图9图示说明化合物C4促进幼稚BV2小胶质细胞中Aβ42的摄取。将BV2细胞用DMSO(运载体)或色甘酸衍生物以5至150μM的不同浓度处理3小时。然后,将细胞与可溶性未标记的Aβ42和DMSO或色甘酸衍生物一起孵育额外的2小时并收集用于ELISA分析。与用运载体处理的细胞相比,用75μM的色甘酸衍生物C4处理的BV2小胶质细胞表现出显著增加的Aβ42摄取水平。
图10图示说明化合物C4促进小胶质细胞BV2-CD33WT中Aβ42的摄取。将稳定表达CD33WT的小胶质细胞用作为对照的DMSO或不同浓度的色甘酸衍生物(C1,C3-8)处理3小时。然后,在Aβ42肽存在下将细胞与DMSO或色甘酸衍生物一起孵育额外的2小时。使用Aβ42特异性ELISA试剂盒分析细胞裂解物的细胞内Aβ42水平。与DMSO处理相比,用75μM的色甘酸衍生物C4处理导致BV2-CD33WT细胞中Aβ42的摄取增加,并且在50μM时显示出剂量依赖性效应。
图11图示说明化合物C4促进BV2-CD33WT细胞中Aβ42的摄取。用不同浓度的DMSO(运载体)或色甘酸衍生物(C1,C2和C4-7)处理BV2-CD33WT细胞3小时。然后,用DMSO或色甘酸衍生物和可溶性Aβ42肽处理细胞2小时。使用Aβ42特异性ELISA试剂盒分析细胞裂解物,并定量细胞内Aβ42水平。与用DMSO处理的细胞相比,50和75μM的色甘酸衍生物C4在BV2-CD33WT细胞中有效诱导Aβ42摄取。
具体实施方式
缺血性中风、阿尔茨海默病(AD)、肌萎缩性脊髓侧索硬化症(ALS或葛雷克氏病)、朊病毒和其他神经退行性疾病与小胶质细胞激活和肥大细胞迁移有关,也与单核细胞和产生一连串增加炎症的毒性细胞因子和碎片的其他细胞类型有关。在某些实施方案中,本发明包括抗炎化合物,通过将小胶质细胞从促炎M1状态转变为M2状态来降低促炎细胞因子的毒性作用,所述M2状态时毒性作用降低并且其对淀粉样变性、tau蛋白病和其他细胞毒性事件的吞噬活性增强。在某些实施方案中,本发明还包括化合物在影响疾病过程中的早期治疗的用途。
许多用作抗炎剂的药物在将小胶质细胞从M1转化为M2方面没有显示出效力,它们也没有增强小胶质细胞从M1到M2的调节。就本申请人所知,本文所述的化合物是具有M1至M2活性的唯一有效的、非细胞因子(例如IL-10)化合物。因此,在某些实施方案中,本发明包括化合物以及通过给予治疗有效量的至少一种所述化合物治疗神经元炎症病症的方法。
在某些实施方案中,本发明的化合物包括具有下式的那些化合物及其类似物和异构体:
此外,X可包括但不限于卤素和OCO(C1-C8烷基)。烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基和戊基。卤素包括氟、氯、溴和碘。Y可包括但不限于-CH2OH、-CH2OAc或-CH2OMe。优选地,本发明的化合物包括在5位连接的那些化合物。
在本发明范围内的具体化合物包括:
色甘酸二钠;
F-色甘酸二酸;
ET-色甘酸;
/>
F-ET-色甘酸;
三醇-色甘酸;
F-三醇-色甘酸;
Ac-三醇-色甘酸;或
POM-色甘酸;或
在某些实施方案中,化合物还包括5-[3-(2-羧基-4-氧代色烯-5-基)氧基-2-羟基丙氧基]-4-氧代色烯-2-羧酸衍生物和异构形式。
在某些实施方案中,本发明包括治疗多种神经元炎症病症的方法。神经元炎症病症包括但不限于诸如ALS、自闭症谱系障碍(ASD)、缺血性中风和朊病毒病的疾病。在某些实施方案中,所述化合物可用于治疗ALS,包括但不限于减缓或停止疾病的进展。在某些实施方案中,化合物可以与其他抗炎剂组合给予,以控制ALS的进行性和致命性作用的扩散。
在某些实施方案中,本发明包括针对ALS用于控制神经炎症的M1,M2转化活性药物与其他免疫靶向疗法的组合治疗,所述用于控制神经炎症的M1,M2转化活性药物例如上式中的药物,所述其他免疫靶向疗法例如CD4+,siRNA,改善ALS的miRNA,胶质形态调节剂,SOD1控制物或利鲁唑(唯一批准用于ALS的药物)。
在其他实施方案中,化合物针对位于脑干和/或脊髓、神经元或影响自发性身体肌肉的运动神经元中的神经元将减缓或停止神经元损伤。
在某些实施方案中,化合物可以使用已知的药物给药方法给药,例如IP,IV,透皮,吸入。在某些实施方案中,本发明涉及治疗或减缓神经疾病(例如AD,缺血性中风,ALS或朊病毒)的侵袭性进展的方法,并且该化合物通过输注或腹膜内给予来施用。
在某些实施方案中,本发明还提供药物组合物,其包含一种或多种本文所述的化合物以及药学上可接受的载体。优选这些组合物可以是单位剂型,例如片剂、丸剂、胶囊、粉末剂、颗粒剂、无菌胃肠外溶液剂或混悬剂、计量气溶胶或液体喷雾剂、滴剂、安瓿、自动注射器装置或栓剂,用于口服、胃肠外、鼻内、舌下或直肠给药、或者用于通过吸入或吹入给药。还设想可将化合物掺入透皮贴剂中,所述透皮贴剂设计成以连续方式递送适量的药物。
为了制备固体组合物如粉末和片剂,将主要活性成分与药学上可接受的载体如常规的压片成分如玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙或树胶,以及其他药物稀释剂如水进行混合,以形成含有均质混合物的固体预配制组合物。这些预配制组合物是均质的描述是指活性成分均匀分散在整个组合物中,使组合物可容易地再细分成同等有效的单位剂型。
在一些实施方式中,将干粉组合物微粉化以吸入肺部。参见例如美国专利申请公开2016/0263257,其全部内容通过引用明确并入本文,特别是关于其中所述的干粉色甘酸制剂。在其他实施方案中,干粉组合物还包含至少一种赋形剂。在某些实施方案中,所述至少一种赋形剂包括乳糖一水合物和/或硬脂酸镁。
在某些实施方案中,化合物可以以治疗具体适应症的剂量给予。具体说,剂量经特别定制以使血液、脑和CSF浓度能够让药物充当M1至M2调节物的作用。这样的剂量可以包括每天约1mg至约1000mg。
活性剂的剂量通常取决于许多因素,包括化合物的药效学特征,化合物的给药方式和途径,所治疗患者的健康状况,所需治疗的程度,(如果有的话)并行治疗的性质和种类,治疗的频率和所需效果的性质。通常,化合物的剂量范围通常为每天约0.001至约250mg/kg体重。对于体重约70kg的正常成人,剂量可以为约0.1至约25mg/kg体重。然而,根据所治疗的对象的年龄和体重,预期的给药途径,所施用的特定药剂等,可能需要该常规剂量范围的一些变化。重要的是,本领域普通技术人员阅读本文后完全能够确定特定哺乳动物的剂量范围和最优剂量。
化合物的剂量可低至5ng/天。在某些实施方案中,给予约10ng/天、约15ng/天、约20ng/天、约25ng/天、约30ng/天、约35ng/天、约40ng/天、约45ng/天、约50ng/天、约60ng/天、约70ng/天、约80ng/天、约90ng/天、约100ng/天、约200ng/天、约300ng/天、约400ng/天、约500ng/天、约600ng/天、约700ng/天、约800ng/天、约900ng/天、约1μg/天、约2μg/天、约3μg/天、约4μg/天、约5μg/天、约10μg/天、约15μg/天、约20μg/天、约30μg/天、约40μg/天、约50μg/天、约60μg/天、约70μg/天、约80μg/天、约90μg/天、约100μg/天、约200μg/天、约300μg/天、约400μg/天约500μg/天、约600μg/天、约700μg/天、约800μg/天、约900μg/天、约1mg/天、约2mg/天、约3mg/天、约4mg/天、约5mg/天、约10mg/天、约15mg/天、约20mg/天、约30mg/天、约40mg/天或约50mg/天的化合物。
活性剂的剂量范围可以是5ng/天至100mg/天。在某些实施方式中,活性剂的剂量范围可以是约5ng/天至约10ng/天、约15ng/天、约20ng/天、约25ng/天、约30ng/天、约35ng/天、约40ng/天、约45ng/天、约50ng/天、约60ng/天、约70ng/天、约80ng/天、约90ng/天、约100ng/天、约200ng/天、约300ng/天、约400ng/天、约500ng/天、约600ng/天、约700ng/天、约800ng/天或约900ng/天。在某些实施方式中,化合物的剂量范围可以是约1μg/天至约2μg/天、约3μg/天、约4μg/天、约5μg/天、约10μg/天、约15μg/天、约20μg/天、约30μg/天、约40μg/天、约50μg/天、约60μg/天、约70μg/天、约80μg/天、约90μg/天、约100μg/天、约200μg/天、约300μg/天、约400μg/天、约500μg/天、约600μg/天、约700μg/天、约800μg/天或约900μg/天。在某些实施方式中,活性剂的剂量范围可以是约1mg/天至约2mg/天、约3mg/天、约4mg/天、约5mg/天、约10mg/天、约15mg/天、约20mg/天、约30mg/天、约40mg/天、约50mg/天、约60mg/天、约70mg/天、约80mg/天、约90mg/天、约100mg/天、约200mg/天、约300mg/天、约400mg/天、约500mg/天、约600mg/天、约700mg/天、约800mg/天或约900mg/天。
在某些实施方式中,以pM或nM的浓度给予化合物。在某些实施方式中,以约1pM、约2pM、约3pM、约4pM、约5pM、约6pM、约7pM、约8pM、约9pM、约10pM、约20pM、约30pM、约40pM、约50pM、约60pM、约70pM、约80pM、约90pM、约100pM、约200pM、约300pM、约400pM、约500pM、约600pM、约700pM、约800pM、约900pM、约1nM、约2nM、约3nM、约4nM、约5nM、约6nM、约7nM、约8nM、约9nM、约10nM、约20nM、约30nM、约40nM、约50nM、约60nM、约70nM、约80nM、约90nM、约100nM、约300nM、约400nM、约500nM、约600nM、约700nM、约800nM或约900nM的浓度给予化合物。
在某些实施方案中,剂型是固体剂型,并且剂型中化合物的大小是重要的。在某些实施方案中,化合物的直径小于约3μm,小于约2μm,或小于约1μm。在某些实施方案中,活性剂的直径为约0.1μm至约3.0μm。在某些实施方案中,活性剂的直径为约0.5μm至约1.5μm。在某些实施方案中,活性剂的直径为约0.2μm、约0.3μm、约0.4μm、约0.5μm、约0.6μm、约0.7μm、约0.8μm、约0.9μm、约1.0μm、约1.1μm、约1.2。μm、约1.3μm、约1.4μm、或约1.5μm。
例如,用于口服给予人的制剂可含有约0.1mg至约5g活性剂(或化合物),其与占组合物总量的约5%至约95%的合适且方便的载体材料复配。单位剂量通常含有约0.5mg至约1500mg活性剂。剂量可以是约:1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg 25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg 35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、55mg、60mg、65、mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或100mg等,一直到约1500mg的化合物。
在某些实施方案中,本发明涉及两种活性剂的组合。在某些实施方案中,与第二组分相比,药物组合包含相对大量的第一组分可能是有利的。在某些情况下,第一活性剂与第二活性剂的比率为约:200:1、190:1、180:1、170:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、30:1、20:1、15:1、10:1、9:1、8:1、7:1、6:1或5:1。进一步优选具有更均等的药物试剂分布。在某些情况下,第一活性剂与第二活性剂的比率为约:4:1、3:1、2:1、1:1、1:2、1:3或1:4。与第一组分相比,药物组合具有相对大量的第二组分也可能是有利的。在某些情况下,第二活性剂与第一活性剂的比率为约200:1、190:1、180:1、170:1、160:1、150:1、140:1、130:1、120:1、110:1、100:1、90:1、80:1、70:1、60:1、50:1、40:1、30:1、20:1、15:1、10:1、9:1、8:1、7:1、6:1或5:1。包含第一治疗剂与第二治疗剂的上述任意组合的组合物可以每天1、2、3、4、5、6或更多次的分开剂量给予或者以提供有效于获得所需结果的释放速率的形式给予。剂型可含有第一和第二活性剂。如果剂型含有第一和第二活性剂,则每天可以给药一次。
例如,意在对人经口给予的制剂可含约0.1mg至约5g的第一治疗剂和约0.1mg至约5g的第二治疗剂,两者与合适且方便的量的载体材料混合,该载体材料占全部组合物的约5%至约95%。单位剂量通常含有约0.5mg至约1500mg的第一治疗剂和0.5mg至1500mg的第二治疗剂。剂量可以是约:25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或100mg等,一直到约1500mg的第一治疗剂。剂量可以是约:25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或100mg等,一直到约1500mg的第二治疗剂。
在某些实施方案中,本发明涉及治疗阿尔茨海默病的方法,包括每天通过吸入给予有需要的患者包含约1mg至100mg色甘酸二钠的微粉化干粉。
实施例
实施例1
我们在PS1/PSS动物模型中的研究表明,色甘酸钠影响小胶质细胞与淀粉样蛋白沉积物的相互作用,并最终影响小胶质细胞的Aβ清除。我们首先在用PBS或最高剂量的色甘酸钠(3.15mg/kg)处理的小鼠的脑切片中进行Aβ和小胶质细胞标记物Iba1之间的双重免疫染色。对两种染色之间重叠的系统分析显示,接受色甘酸钠的动物显示出与淀粉样蛋白重叠的较高百分比的Iba1免疫反应性(图1B),这可能表明该化合物诱导的斑块周围小胶质细胞的适度增加。
为了进一步了解这些机制,并考虑到评估小胶质细胞功能的变化在体内具有挑战性,我们使用了额外的体外Aβ小胶质细胞摄取系统。在存在或不存在色甘酸钠的情况下,将合成的Aβ40和Aβ42肽应用于培养中的小胶质细胞。
孵育16小时后,我们观察到在色甘酸钠存在下Aβ40和Aβ42水平的剂量依赖性降低,表明色甘酸钠对Aβ聚集机制的影响可通过小胶质细胞摄取促进Aβ清除(图1C)。体内和体外结果的组合可能表明,除了抑制Aβ原纤维化外,色甘酸钠还影响小胶质细胞活化和Aβ清除。
色甘酸钠不影响血浆中的Aβ水平,但促进小胶质细胞Aβ清除。图1A说明用PBS或递增剂量的色甘酸钠处理一周后对Aβx-40和Aβx-42的血浆水平的定量(n=3-5只小鼠/组)。图1B示出了在用色甘酸钠(3.15mg/kg)或PBS每天处理持续7天的小鼠中淀粉样蛋白沉积物(6E10)和小胶质细胞(Iba1)的定位的代表性图像。计算每个沉积物的Iba1阳性过程占淀粉样蛋白的百分比,其显示出在用色甘酸钠处理后Aβ和Iba1之间的重叠增加(对于PBS,n=3只小鼠,对于色甘酸钠,n=5只小鼠)。对每只动物评估20对20个斑块。比例尺=10μm。图1C显示了色甘酸钠对小胶质细胞体外Aβ摄取的影响。培养小胶质细胞并与50nM合成的Aβ40或Aβ42以及0、10nM、10μM或1mM的色甘酸钠一起孵育16小时。孵育后,使用AβELISA测量培养基中Aβx-40(图1C左)Aβx-42(图1C,右)的浓度,并用小胶质细胞数和根据PBS对照条件标准化。(n=3次实验;*,P<0.05,**,P<0.01)
实施例2
在小胶质细胞激活和M1,M2转化的其他动物研究中显示,色甘酸是测试的许多药物中唯一影响这种变化并表现出吞噬活性的药物。图2显示了该研究的Tg-2576小鼠中所有斑块和围绕这些沉积物的小胶质细胞的代表性斑块。观察与淀粉样蛋白染色共定位的Iba-1阳性过程相对于斑块周围的Iba-1信号总量的百分比的图像分析表明,与任意其他组相比,当用色甘酸钠处理小鼠时,Iba-1/淀粉样蛋白共定位更多。该结果与实施例1中的结果以及我们的体外数据相关联。
色甘酸促进小胶质细胞Aβ42摄取(但布洛芬不行),它们的组合改善了单独的布洛芬或色甘酸导致的摄取。用色甘酸和/或布洛芬(10μM,100μM,1mM)处理BV2小胶质细胞培养物16小时。然后,将细胞与可溶性Aβ42和化合物一起孵育3小时。孵育后,收集细胞用于ELISA分析。用色甘酸(100μM,1mM)以及用色甘酸和布洛芬(每种化合物100μM,1mM)处理的BV2小胶质细胞相对于用运载体处理的BV2小胶质细胞表现出增加的Aβ42摄取水平。结果来自三个独立的实验;**p<0.01,***p<0.001,单因素方差分析,Tukey检验)。数据表示为平均值±SEM。图3图示显示用色甘酸处理的BV2小胶质细胞的结果,并且相对于用运载体处理的BV2小胶质细胞,用色甘酸和布洛芬处理表现出增加的Aβ42摄取水平。
实施例3:化合物合成
5,5'-[(2-羟基-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸二乙
酯
将色甘酸钠盐(1.0g,2mmol)在EtOH(100mL)和浓盐酸(1mL)中的悬浮液在密封的反应器管中于100℃加热24小时。白色固体溶解,趁热得到澄清的无色溶液。将其冷却至室温并加入NaHCO3(1.0g)。在25℃下搅拌30分钟后,通过旋转蒸发除去溶剂。用5:95甲醇/二氯甲烷在硅胶上进行色谱分离,得到二乙酯(0.8g,产率76%);熔点154-156℃;1H NMR(CDCl3,300MHz)δ1.42(t,3H,J=7.1Hz,CH3),2.73(br s,1H,OH),4.44(q,4H,J=7.1Hz,2OCH2CH3),4.32-4.59(m,5H,CHOH,2OCH2),6.80(s,2H,2乙烯基-H),6.99(d,2H,J=8.24Hz,2Aro-H),7.12(d,2H,J=8.24Hz,2Aro-H),7.17(d,2H,J=8.24Hz,2Aro-H),7.71(t,2H,J=8.24 2Aro-H)。
5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸二乙酯
3-双(4-甲基苯磺酸酯)-2-氟丙二醇
二氯甲烷(20mL)中的1,3-双(4-甲基苯磺酸)丙三醇(2.7g,6.78mmol)溶液于0-5℃用DAST(2.18g,13.6mmol)处理。将混合物在0-5℃下搅拌30,然后温热至25℃并搅拌16小时。将混合物倒入饱和碳酸氢钠溶液(30mL)中并分层。二氯甲烷层干燥(硫酸钠)。除去溶剂后,将粗产物在硅胶上进行色谱分离(二氯甲烷),得到0.82g(30%)固体;熔点99-102℃;1HNMR(CDCl3),δ2.5(s,6H,CH3),4.15(dd,4H,J=12.3,4.6Hz,CH2,4.8(dq,1H,J=47,4.6,CHF),7.45(d,4H,J=8.1Hz,Aro-H),7.75(d,4H,J=8.4Hz,Aro-H)。
5,5’-(2-氟丙烷-1,3-二基)双(氧基)双(4-氧代-4H-色烯-2-羧酸)
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1,3-双(2-乙酰基-3-羟基苯氧基)-2-氟丙烷
乙腈(40mL)中的3-双(4-甲基苯磺酸)-2-氟丙二醇(1.0,2.5mmol),2,6-二羟基苯乙酮(0.76g,5.0mmol)和碳酸钾(0.69g)的混合物回流加热16小时。过滤该反应混合物,并蒸发滤液。将粗产物在硅胶上进行色谱分离(乙腈/二氯甲烷5:95),得到0.57g(40%)产物;熔点162-165℃;1H NMR(d6-DMSO),δ2.5(s,6H,2CH3),4.38(m,4H,2CH2),5.22(br d 1H,J=49Hz,CHF),6.45(m,4H,4Aro-H),7.28(t,2H,J=4.55Hz,2Aro-H)。
5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸二乙酯
1,3-双(2-乙酰-3-羟基苯氧基)-2-氟丙烷(200mg,0.52mmol)和草酸乙酯(2mL)的混合物加入乙醇(10mL)和苯(10mL)中的乙氧基钠(87mg Na)溶液中。将混合物回流加热16小时,冷却并用醚(50mL)稀释。过滤沉淀的钠盐,用醚洗涤并干燥。然后将其溶于水中并用10%HCl酸化,得到粘性固体。将固体在乙醇(20mL)中与催化量的36%HCl一起回流1小时。混合物倒入50mL水中并用二氯甲烷(50mL)萃取两次。合并萃取物并干燥。除去溶剂后,将粗产物在硅胶上进行色谱分离(乙腈/二氯甲烷10:90),得到0.12g(45%)产物;熔点166-170℃;1H NMR(CDCl3),δ1.42(t,6H,J=7.14Hz,2CH3),4.58(q,4H,J=7.14Hz 2CH2),4.65(m,4H,2CH2),5.35(dq,1H,J=46Hz,J=4.4HZ,CHF),6.90(s,2H,乙烯基-H),6.95(d,2H,J=8.24Hz,2Aro-H),7.13(d,2H,J=8.24Hz,2Aro-H),7.17(d,2H,J=8.24Hz,2Aro-H)7.6(t,2H,J=8.24 2Aro-H)。
5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸
将5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸二乙酯(100mg,0.19mmol)在甲醇(20mL)中的悬浮液和1M氢氧化钠(2mL)在80℃加热1小时。用10% HCl酸化溶液并去除挥发物。向所述固体加入甲醇/二氯甲烷(50:50)的溶液并过滤混合物。蒸发得到76mg(85%)产物;1H NMR(d6-DMSO),δ4.65(m,4H,2CH2),5.32(br d,1H,J=46Hz,CHF),6.80(s,2H,2乙烯基-H),7.2(d,2H,J=8.24Hz,2Aro-H),7.71(t,2H,J=8.242Aro-H)。
5,5'-[(2-羟基-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃--2-乙醇
向5,5'-(2-羟基三亚甲基二氧基)双(4-氧代色烯-2-羧酸)二乙酯(1.0g,1.86mmol)在甲醇(60ml)和二氯甲烷(40mL)的悬浮液中在1小时内分批加入NaBH4(0.14g,3.72mmol)。将混合物在25℃下搅拌直至澄清(约5小时),此时通过逐滴加入1M HCl淬灭溶液直至呈酸性。蒸发溶剂,残余物用二氯甲烷萃取。将合并的有机萃取液用水洗涤并用无水硫酸钠干燥。蒸发后,残余物用柱色谱(5:95甲醇/二氯甲烷)纯化,得到0.5g(50%)三醇;1HNMR(DMSO-d6,300MHz)δ2.73(s,3H,OH),4.25-4.36(m,9H,2OCH2,CH-O),6.13(s,2H,2乙烯基H),7.04(d,2H,J=8.4Hz,芳族H),7.07(d,2H,J=8.4Hz,芳族H),7.63(t,2H,J=8.2Hz,芳族H)。
5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃--2-乙醇
使用上述制备5,5'-(2-羟基三亚甲基二氧基)双(4-氧代色烯-2-乙醇)的方法。1HNMR(DMSO-d6,300MHz)δ2.73(s,3H,OH),4.25-4.36(m,8H,2OCH2,CH-O),5.35(br d,1H,J=46Hz,CHF),6.13(s,2H,2乙烯基H),7.04(d,2H,J=8.4Hz,芳族H),7.07(d,2H,J=8.4Hz,芳族H),7.63(t,2H,J=8.2Hz,芳族H)。
5,5'-[(2-羟基-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸双
[(2,2-二甲基-1-氧代丙氧基)甲基]酯
向搅拌的色甘酸二酸(1.0g,2.7mm)在20mL DMF中的溶液中加入二异丙胺(0.7mL)和1.0g(6.5mmol)新戊酸氯甲酯。将反应混合物在60℃下搅拌4小时,加入水,分离萃取混合物,干燥(MgSO4)并真空除去溶剂。除去溶剂,残余物在硅胶4%甲醇/二氯甲烷中进行色谱分离,得到1.2g(65%)新戊酸酯化合物;mp(熔点)135-140℃;H1 NMR(CDCl),δ1.24(s,18H,CH3),4.36(m,2H,OCH2),4.49(m,1H,CHOH),4.51(m,2H,OCH2),),6.00(s,4H,CH-O-CO),6.98(m,4H,2乙烯基-H,2Aro-H),7.13(d,2H,J=8.24Hz,2Aro-H),7.61(t,2H,J=8.24 2Aro-H)。
5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸双[(2,
2-二甲基-1-氧代丙氧基)甲基]酯
向搅拌的5,5'-[(2-氟-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-羧酸(1.0g,2.1mmol)在20mL DMF的溶液中加入异丙胺(0.7mL)和1.0g(6.5mmol)新戊酸氯甲酯。将反应混合物在60℃下搅拌4小时,加入水,分离萃取混合物,干燥(MgSO4)并真空除去溶剂。除去溶剂,残余物在二氧化硅上用2%甲醇的二氯甲烷溶液进行色谱分离,得到1.0g(70%)新戊酸酯化合物;熔点130-133℃;δ1.21(s,18H,CH3),4.36(m,4m,2OCH2),4.49(brd,1H,J=46Hz,CHF),6.00(s,4H,CH-O-CO),6.98(m,4H,2乙烯基-H,2Aro-H),7.13(d,2H,J=8.24Hz,2Aro-H),7.61(t,2H,J=8.24 2Aro-H)。
5,5'-[(2-羟基-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃--2-乙醇的三
乙酸酯
将乙酸酐(0.5g,4.6mmol))缓慢加入到冷却至0-5℃的5,5'-[(2-羟基-1,3-丙二基)双(氧基)]双[4-氧代-4H-1-苯并吡喃-2-乙醇(0.5g,1.14mmol)的吡啶(20mL)混合物中。将混合物在0-5℃下搅拌3小时,然后温热至室温。TLC指示反应完成。加入二氯甲烷,用10%HCl洗涤混合物直至水相呈酸性。用无水硫酸钠干燥二氯甲烷层,蒸发溶剂。用3%甲醇/二氯甲烷在硅胶上进行色谱分离,得到0.45g(72%)三乙酸酯化合物;熔点122-125℃;H1 NMR(CDCl3),δ2.16(s,9H,CH3),4.58(m,2H,CH2OH),4.66(m,2H,CH2OH),4.94(s,4H,CH2OH),5.66(m,1H,CHOH),6.15(s,2H,2乙烯基-H),6.94(d,2H,2Aro-H),6.97(d,2H,J=8.24Hz,2Aro-H),7.52(t,2H,J=8.24,2Aro-H)。
实施例4:Aβ聚集抑制测定
实验设计。使3个月大的Tg2576小鼠适应2个月,然后随机分配到不同的处理组。它们包括对照组(n=10)用运载体处理,色甘酸低剂量组和色甘酸高剂量组。通过基于0.1mL/30g体重用PBS通过IP注射进行处理,每周3次,再进行3个月。所有小鼠在8个月大时处死。收获组织并处理以进行死后分析。
将最终5μM的合成Aaβ42与10、100、1,000nM的测试化合物一起孵育1小时。用最终浓度为0.5mg/ml的肝素引发聚集。测定缓冲液由125mM NaCl,2.5mM KCl,1mM MgCl2,1.25mMNa2H2PO4,2mM CaCl2,25mM葡萄糖和NaHCO3组成,将pH调节至7.4。测定缓冲液用作对照。通过硫黄素T结合的强度测量聚集,其以动力学模式检测450nm/480nm的荧光激发/发射(Spectra Max M3平板读数器,Molecular Devices)。记录聚集,通过平板读数器的软件将动力学计算为V最大。该测定一式三份进行,并表示为标准平均值±SD。蓝色虚线表示测定缓冲液对照。图4显示了测定结果。
实施例5
色甘酸显著影响脑TBS可溶性Aβ的水平和Aβ(42:40)的比率。A-B.MSD(用于测量Aβ42、40和38的混乱量表)Aβ测定应用于脑TBS可溶性样品。测定了比较各个处理组的Aβ水平和Aβ比率(42:40)的差异。*p<0.05;**p<0.01,***p<0.001,单因素方差分析,Tukey检验;平均值±SEM显示,对于低剂量和高剂量的色甘酸和布洛芬组合,较高相对水平的Aβ42/40和更高的不涉及斑块形成的Aβ38。图5图示说明了Aβ水平和Aβ比率(42:40)的单向差异结果。
实施例6-色甘酸钠对小胶质细胞中Aβ42摄取的影响
使用共聚焦显微镜和ELISA测定评估色甘酸及其衍生化合物对小胶质细胞中Aβ42摄取的影响。使用BV2小胶质细胞系,其先前被发现有效地摄取和降解外源添加的Aβ42(Jiang,Q.等人(2008)Neuron 58,681–693;Mandrekar等人,2009J.Neurosci.29,4252–4262)。在幼稚BV2小胶质细胞中测试化合物以研究它们是否调节Aβ摄取。评估化合物在稳定表达全长人CD33的BV2细胞(BV2-CD33WT)中的作用,以探究它们是否逆转CD33介导的Aβ摄取抑制(Griciuc等,2013Neuron 78,631-643)。
储备溶液的化合物编号,分子量和浓度总结在表1中。与色甘酸衍生物C1,C2,C5,C6,C7和C8相比,色甘酸衍生物C3和C4在DMSO中显示出较低的溶解度。因此,制备了除C3和C4之外的所有化合物的25mM储备溶液。分别以5mM和7.5mM的浓度制备C3和C4的储备溶液。C1是母体化合物-色甘酸二钠。
表1:在小胶质细胞中测试的化合物的总结
化合物编号 | 化合物名称 | 储备溶液(mM) |
C1 | 色甘酸二钠 | 25 |
C2 | F-色甘酸二酸 | 25 |
C3 | ET-色甘酸 | 5 |
C4 | F-ET-色甘酸 | 7.5 |
C5 | 三醇-色甘酸 | 25 |
C6 | F-三醇-色甘酸 | 25 |
C7 | Ac-三醇-色甘酸 | 25 |
C8 | POM-色甘酸 | 25 |
为了研究色甘酸钠对小胶质细胞中Aβ42摄取的影响,将幼稚BV2细胞用DMSO(对照)或色甘酸以500μM处理16小时。然后,用PBS洗涤细胞,并在荧光标记的Aβ42肽(400nM,红色)存在下用DMSO或色甘酸处理2小时。在处理结束时,洗涤细胞并用质膜染料(绿色)标记它们。使用共聚焦显微镜和红色通道中的荧光信号,定量细胞内Aβ42肽的水平。所有定量均由盲观察者用ImageJ软件进行。值得注意的是,色甘酸钠导致幼稚BV2小胶质细胞中Aβ42的摄取增加(图6A-图6D)。
此外,通过使用ELISA测定法测定色甘酸钠是否调节幼稚BV2小胶质细胞中的Aβ42摄取。另外,确定色甘酸钠是否导致稳定表达全长人CD33的BV2细胞(BV2-CD33WT)中Aβ42摄取水平增加。为此目的,将幼稚BV2和BV2-CD33WT细胞系用DMSO(对照)或不同浓度的色甘酸处理16小时。然后,用PBS洗涤细胞,并用DMSO或色甘酸和可溶性未标记的Aβ42肽(400nM)处理2小时。使用来自Wako的Aβ42特异性ELISA试剂盒分析收集的细胞裂解物的Aβ42摄取水平。将ELISA结果标准化为先前使用BCA测定法定量的蛋白质浓度水平。
在幼稚BV2小胶质细胞中,色甘酸钠在100μM和1mM导致Aβ42摄取增加(图7A),因此通过ELISA测定证实了免疫荧光结果。色甘酸钠还导致BV2-CD33WT细胞中在10μM和500μM的内化的Aβ42水平增加(图7B,ELISA测定)并逆转CD33介导的小胶质细胞中Aβ42摄取的抑制。总之,用色甘酸钠处理在调节幼稚BV2和BV2-CD33WT细胞系中的Aβ42摄取水平方面显示出剂量依赖性效应。
实施例7-色甘酸衍生物对小胶质细胞中Aβ42摄取的影响
为了研究色甘酸衍生物对小胶质细胞中Aβ42摄取的影响,将幼稚BV2或BV2-CD33WT细胞接种在增殖培养基中。第二天,将细胞用DMSO(对照)或不同浓度的化合物在增殖培养基中处理3小时。在10,50,100和150μM下测试C1,C2,C5,C6,C7和C8,而由于DMSO中的溶解度限制,在5,25,50和75μM下评估C3和C4。然后,用PBS洗涤细胞,并在未标记的Aβ42肽(400nM)存在下,在DMEM培养基中用DMSO或化合物处理2小时。在用CytoTox-ONETM乳酸脱氢酶(LDH)测定法评估在处理结束时收集的培养基中的化合物毒性。用冷PBS洗涤平板中剩余的细胞,并用补充有蛋白酶和磷酸酶抑制剂的RIPA缓冲液裂解。使用PierceTM BCA蛋白质测定试剂盒测定裂解物上清液中的蛋白质浓度,并使用来自Wako的Aβ42ELISA试剂盒分析来自每种裂解物的2-3μg/孔的总蛋白质的Aβ42摄取。进一步研究排除了有毒化合物浓度。
为了研究色甘酸衍生物是否在较高剂量下诱导细胞毒性,将幼稚BV2小胶质细胞与DMSO(运载体)或不同浓度的色甘酸衍生物一起孵育3小时。然后洗涤细胞并与DMSO或化合物和可溶性未标记的Aβ42一起孵育额外的2小时。然后,收集细胞培养基并测量受损细胞释放的LDH以鉴定诱导细胞溶解的化合物。LDH测定显示,当在100和150μM下测试时,色甘酸衍生物C8是唯一显示出毒性的化合物(图8)。因此,C8的100和150μM浓度被排除在Aβ42摄取测定之外。
实施例8-通过色甘酸衍生物调节小胶质细胞中Aβ42的摄取
为了测试色甘酸衍生物是否调节Aβ42摄取,将幼稚BV2小胶质细胞用DMSO(对照)或不同浓度的色甘酸衍生物化合物处理3小时。然后,洗涤细胞并在未标记的Aβ42肽存在下用DMSO或化合物处理2小时。在处理结束时,收集细胞裂解物。使用Aβ42特异性ELISA试剂盒进行细胞内Aβ42水平的分析。母体化合物C1(色甘酸钠)在100和150μM导致BV2细胞中的Aβ42摄取适度增加。与其他色甘酸衍生物一起接收的C1等分试样在DMSO中的溶解度低于首次送至我们的C1等分试样(不含色甘酸衍生物)。有趣的是,化合物C6导致BV2小胶质细胞中Aβ42摄取的强烈抑制。值得注意的是,在幼稚BV2小胶质细胞中色甘酸衍生物C4在75μM导致Aβ42肽摄取增加(图9)。
此外,通过两组独立的实验确定色甘酸衍生物是否影响BV2-CD33WT细胞中的Aβ42摄取和清除。用DMSO(对照)或浓度范围为5-150μM的色甘酸衍生物处理BV2-CD33WT细胞。
在第一组实验中,测试了色甘酸衍生物C1和C3-8。在第二组实验中用其他色甘酸衍生物测试化合物C2。与DMSO处理相比,用75μM的化合物C4处理导致Aβ42摄取增加两倍,并且在50μM时显示出剂量依赖性效应(图10)。使用GraphPad Prism 7软件,BV2-CD33WT细胞中C4的IC50为54.7μM。与DMSO处理相比,化合物C6在介导BV2-CD33WT细胞中Aβ42摄取的抑制中表现出剂量依赖性作用。
在第二组实验中,测试了BV2-CD33WT细胞中的色甘酸衍生物C1,C2和C4-7。这些结果证实了先前的结果,即与DMSO处理相比,化合物C4在75μM时增加Aβ42摄取最有效,并且在较低浓度下显示出剂量依赖性效应(图11)。因此,这些结果表明化合物C4导致BV2-CD33WT细胞中Aβ42摄取水平增加并逆转CD33介导的对Aβ摄取和清除的抑制(图10和11)。
这些结果表明,色甘酸衍生物C4诱导小胶质细胞摄取和清除Aβ42,并增强小胶质细胞从神经毒性/促炎性向神经保护/促吞噬活化表型的倾斜。
Claims (10)
1.至少一种具有下式的化合物在制备用于治疗神经元炎症病症的药物中的应用:
前提是当神经元炎症病症为阿尔茨海默病(AD)时,所述化合物不是色甘酸二钠,F-色甘酸二钠,ET-色甘酸或F-ET-色甘酸。
2.如权利要求1所述的应用,其中,所述化合物具有下式:
色甘酸二钠;
F-色甘酸二酸;
ET-色甘酸;
F-ET-色甘酸;
三醇-色甘酸;
F-三醇-色甘酸;
Ac-三醇-色甘酸;
POM-色甘酸;或
3.如权利要求1或2所述的应用,其中,所述神经元炎症病症是肌萎缩侧索硬化症(ALS)。
4.如权利要求1所述的应用,其中,所述神经元炎症病症是肌萎缩侧索硬化症(ALS);并且所述化合物具有下式:
5.如权利要求1所述的应用,其中,所述神经元炎症病症是肌萎缩侧索硬化症(ALS);并且所述化合物具有下式:
6.如权利要求1所述的应用,其中,所述神经元炎症病症是肌萎缩侧索硬化症(ALS);并且所述化合物具有下式:
7.如权利要求1所述的应用,其中,所述神经元炎症病症是肌萎缩侧索硬化症(ALS);并且所述化合物具有下式:
8.如权利要求1所述的应用,其中,所述神经元炎症病症是肌萎缩侧索硬化症(ALS);并且所述化合物具有下式:
9.如权利要求1或2所述的应用,其中,所述神经元炎症病症是AD。
10.如权利要求1或2所述的应用,其中,所述神经元炎症病症是亨廷顿病。
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CN109922800B (zh) | 2023-06-13 |
EP3506894A4 (en) | 2020-07-29 |
EP3506894C0 (en) | 2023-08-23 |
US20240082207A1 (en) | 2024-03-14 |
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JP2022171666A (ja) | 2022-11-11 |
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