CN102046168A - 用于治疗眼部病症的pai-1表达和活性抑制剂 - Google Patents
用于治疗眼部病症的pai-1表达和活性抑制剂 Download PDFInfo
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Abstract
本发明在一个实施方式中涉及在患者中治疗青光眼和升高的IOP的方法,其包括对患者施用有效量的组合物,所述组合物包含抑制PAI-1表达或PAI-1活性的试剂。本发明另一个实施方式是在有需要的受试者中治疗与PAI-1相关的眼部病症的方法,其包括对患者施用有效量的组合物,所述组合物包含抑制PAI-1表达或PAI-1活性的试剂。
Description
相关申请的交叉引用
本申请是于2007年10月31日提交的美国申请序列号11/931,393的共同待审批申请的部分继续申请案,所述申请根据35 U.S.C.§120要求优先权,其内容通过引用并入本文。此申请也根据35 U.S.C.§119对2008年4月26日提交的美国申请序列号61/048,176要求优先权,所述申请的全部内容通过引用并入本文。
本发明的技术领域
所述发明总体上涉及用于眼部病症的治疗并且更特别涉及降低IOP和/或治疗或预防青光眼的试剂的用途,所述试剂通过下调PAI-1的表达和活性,由此缓解PAI-1介导的对组织纤溶酶原激活物(t-PA)和或尿激酶纤溶酶原激活物(u-PA)的活性的抑制。
发明背景
原发型开角型青光眼(POAG)是常见的破坏性的眼科疾病,如果不进行治疗会引起进行性的视野丧失。大部分青光眼患者具有升高的眼内压(IOP),而且目前的治疗针对降低IOP升高或维持正常的IOP。
纤溶酶原激活物抑制剂-1(PAI-1)水平的增高似乎在多种疾病状态中起作用,包括癌症、肥胖和糖尿病。在青光眼患者的眼房水中检测到PAI-1水平的升高(Dan等人,Archives of Ophthalmology,Vol.123:220-224,2005)。PAI-1水平被细胞因子TGFβ(Binder等人,News Physiol Sci,Vol.17:56-61,2002)等其他内源刺激所升高。PAI-1抑制组织纤溶酶原激活物(t-PA)和尿激酶纤溶酶原激活物(u-PA)两者的活性。t-PA和u-PA两者都催化纤溶酶原转化为纤溶酶,而这是纤维蛋白溶解级联的关键中间体(Wu等人,Curr Drug Targets,Vol.2:27-42,2002)。已知纤溶酶促进某些前间质金属蛋白酶(MMP)转化成其活性的细胞外基质(ECM)降解形式(He等人,PNAS,Vol.86:2632-2636,1989)。PAI-1也调控玻连蛋白(一种ECM成分)与以粘着受体发挥作用的细胞表面整合素的连接(Zhou等人,Nature Strutural Biology,Vol.10(7):541-544,2003)。因此,已经将PAI-1与非眼部组织中细胞的粘着降低和分离升高相联系。人眼组织也表达不同程度的t-PA和/或u-PA;然而已经报道小梁网(TM)主要表达t-PA(Shuman等人,IOVS,Vol.29:401-405,1988;Tripathi等人,Exp Eye Research,Vol.51:545-552,1990)。t-PA也似乎是在人眼房水(AH)中存在地主要形式。
对降低IOP和/或用于POAG的治疗已经证明有效的药物治疗包括降低眼房水产生的试剂和增加外流便利的试剂。通常通过局部(直接应用至眼睛)或口服这2种可能途径中的一种施用这些治疗。然而,药学眼部抗高压方法已经显示出多种不希望的副作用。例如,缩瞳剂(如匹鲁卡品)可引起视觉模糊、头痛和其他负面的视觉副作用。全身性使用碳酸酐酶抑制剂可引起恶心、消化不良、疲劳和代谢性酸中毒。某些前列腺素引起充血、眼部搔痒以及睫毛和眼眶皮肤的变深。这些负面的副作用可导致患者依从性降低,或者导致治疗的终止从而视觉继续恶化。另外,当用某些现有青光眼疗法治疗时,有些个体完全没有反应。因此,需要其他治疗性试剂用于治疗眼部病症,例如青光眼和眼部高压。
于2006年12月15日提交的并且以美国专利发表号No.2008/0107644发表的美国专利申请号No.11/931,393,公开了调节PAI-1与玻连蛋白结合的试剂作为一种预防小梁网细胞损失并最终降低眼内压的方法的潜在用途。本发明是针对抑制PAI-1对组织纤溶酶原激活物(t-PA)和尿激酶纤溶酶原激活物(u-PA)的作用。
发明概述
本发明的实施方式是针对抑制PAI-1的表达或活性来治疗眼部疾病和/或降低IOP。一个实施方式提供了治疗患者的青光眼或IOP升高的方法,其包括对患者施用有效量的组合物,所述组合物包含抑制PAI-1表达或阻止PAI-1抑制组织纤溶酶原激活物(t-PA)和尿激酶纤溶酶原激活物(u-PA)的活性的试剂。
本发明的另一个实施方式是治疗PAI-1相关眼部病症的方法,其包括施用有效量的组合物,所述组合物包含抑制PAI-1表达和/或抑制PAI-1对t-PA或u-PA活性的作用的试剂。
在这些特定的实施方式中,所述试剂是tiplaxtinin(PAI-039)、diaplasinin(PAI-749)、ZK-4044、WAY-140312、HP-129、T-686、XR5967、XR334、XR330、XR5118、aleplasinin(PAZ-417)、T-2639、S35225、SK216、SK116、2-[2-甲氧基-6-[[[3-(三氟甲基)-4-[4-[3-(三氟甲基)苯基]-1-哌嗪基]苯基]氨基]甲基]苯氧基]-5-对硝基苯甲酸(本文也称作“化合物39”;Ye等,Bioorganic & Medicinal Chemistry Letters,Vol.14(3),761-765,2004)及其组合。其他实施方式可能使用如下试剂SB202190、U0126、SP600125、bisindolylmaleimide I、粗糠柴毒素、SB431542以及SIS3。他汀类试剂例如洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀可用作其他实施方式中的试剂。PAI-1抗体及其肽模拟物也可用于特定的实施方式中。这些试剂的组合也在考虑范围内。
另一个实施方式是制备用于治疗青光眼和升高的IOP的化合物的方法,其包括提供有可能抑制PAI-1的表达或活性的候选物质、通过评估候选物质降低患青光眼或升高的PAI-1的患者的小梁网中的活性构象PAI-1的量的能力来选择所述化合物,以及制备所选择的化合物。
在特定实施方式中,本发明的组合物还包含选自如下的化合物:眼科可接受的防腐剂、表面活性剂、增稠剂、渗透促进剂、凝胶剂、疏水基质、载体、缓冲剂、氯化钠、水及其组合。
在其他实施方式中,可以将选自如下的化合物作为所述组合物的部分或作为单独的施用来施用:β阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳剂、神经保护剂、rho激酶抑制剂及其组合。
上述简要概述广泛地描述了本发明特定实施方式的特性和技术优点。以下本发明详述中将描述其他特性和技术优点。从本发明的详细说明书中,结合任何附图可以更好的理解那些被认为是本发明特征的新特性。然而,本文提供的附图旨在帮助示例说明本发明或者辅助理解本发明,而不旨在限定本发明的范围。
附图简述
通过结合附图参考如下描述可以更完全地理解本发明及其优点。
图1显示TGFβ2(24h)对人小梁网(GTM-3)细胞上清液中PAI-1水平的浓度依赖作用的实验结果。数据表示为平均数和平均数标准误差(SEM),n=3。通过单向方差分析(one-way ANOVA),其后通过Dunnett测试,相对相应的载体组的*p<0.05。
图2显示用或不用TGFβ2(5ng/mL)处理多种时间段的GTM-3细胞上清液中PAI-1水平的实验结果。数据表示为平均数和平均数标准误差,n=3。通过学生t检验,相对相应的载体时间点组的*p<0.05。
图3显示TGFβ2对处理后GTM-3细胞培养上清液中总的和有活性的PAI-1成分的作用。TNFα和地塞米松的作用包括在内作为对照。数据为暴露于检测试剂24小时后的平均数和平均数标准误差;“0”值表示表达水平低于测定的检测极限。
图4显示两个柱状图概括了PAI-1的抑制对GTM-3细胞培养中活性PAI-1的作用。
图5显示了PAI-1合成抑制剂(T-2639)对TGFβ2介导的处理后GTM-3细胞培养上清液中总PAI-1蛋白质水平增加的作用。
图6显示了在I型TGFβ受体抑制剂SB431542存在或不存在的情况下,TGFβ2(5ng/mL)的作用。上图:SB431542(10μM)在多种HTM细胞系中的作用。下图:SB431542对GTM-3细胞的剂量依赖作用。数据为暴露于检测试剂24小时后的平均数和SEM(通过单向方差分其后Bonferroni测试,相对各自的TGFβ2处理后的对照组,*表示p<0.001或**表示p<0.05)。
图7显示在Smad3抑制剂SIS3存在或不存在的情况下,TGFβ2(5ng/mL)的作用(Jinnin等人,Molecular Pharmacology,Vol.69:597-607,2006)。上图:SIS3(10μM)在多种HTM细胞系中的作用。下图:SIS3对GTM-3细胞的剂量依赖作用。数据为暴露于检测试剂24小时后的平均数和SEM(通过单向方差分其后Bonferroni测试,相对各自的TGFβ2处理后的对照组,*表示p<0.001)。
图8显示多种细胞内信号传导通路酶的抑制剂对TGFβ2刺激的GTM-3细胞(上图)和SGTM2697细胞(下图)的作用。所用抑制剂:SB202190(p38MAPK抑制剂)、U0126(MEK1/2抑制剂)、SP600125(JNK抑制剂)、Bisindolylmaleimide I(“Bis I”;PKCα、β、δ、ζ抑制剂)和粗糠柴苦素(PKCδ抑制剂)。数据为暴露于检测试剂24小时后的平均数和SEM(通过单向方差分其后Bonferroni测试,相对TGFβ2处理后的对照组,*表示p<0.001);以及
图9显示他汀类药物对TGFβ2刺激的GTM-3细胞的作用。上图:多种他汀类药物(10μM)的作用。下图:阿托伐他汀的剂量依赖作用。数据为暴露于检测试剂24小时后的平均数和SEM(通过单向方差分其后Bonferroni测试,相对TGFβ2处理后的对照组,*表示p<0.001或**表示p<0.01)
图10是一系列图描述了化合物(tiplaxtinin、diaplasinin和“化合物39”)在细胞外基质清除的替代测定中的作用。所检测化合物在来自6株不同的HTM细胞系每一种的上清液等份试样中引发显而易见超过基本活性(未经处理)的增加。
图11显示两种化合物(tiplaxtinin和diaplasinin)对Ad.TGFβ2诱导的Balb/cJ小鼠的眼内压增加的作用的实验结果,所述两种化合物阻止PAI-1对t-PA和u-PA活性的抑制能力。对于Adv.TGFβ2注射,通过PAI-1抑制剂的预先给药和之后给药实现IOP降低。
图12显示同样这两种PAI-1抑制剂(tiplaxtinin和diaplasinin)对Adv.PAI-1诱导的Balb/cJ小鼠的眼内压增加的作用的实验结果。
发明详述
本发明的特定实施方式是通过干扰与t-PA和u-PA相关的PAI-1活性和/或PAI-1表达来靶向PAI-1在例如青光眼的眼部病症的作用的方法,如下面原理图所示,
其中TGFβ2(或其他刺激物)促进PAI-1基因转录,随之PAI-1蛋白质表达增加并且活性PAI-1的水平增加。活性PAI-1通过t-PA和/或u-PA抑制纤溶酶原转化成纤溶酶。纤溶酶水平随后的减少减低溶解纤维蛋白的能力并增加胞外基质(ECM)的累积。ECM累积增加外流阻力并最终增加IOP。本发明的实施方式确认PAI-1表达的抑制和/或干扰与t-PA和u-PA相关的PAI-1活性是一种有用的青光眼疗法。
抑制PAI-1表达或活性的多种化合物是现有技术已知的。美国专利申请号11/611,312(Fleenor等人,于2006年12月15日提交并发表为美国专利发表号2008/0107644)以及美国专利号7,351,407(Fleenor等人,于2008年4月1日发布)公开了化合物,其可用作抑制PAI-1表达或活性的化合物,并通过引用将其全部并入本文。
本发明的PAI-1抑制剂包括但不局限于,PAI-039(tiplaxtinin)(Crandall等人,Arterioscler Thrombosis Vascular Biology Journal,Vol.26(10):2209-2215,2006);PAI-749(diaplasinin)(Gardell等人,Molecular Pharmacology,Vol.72(4):897-906,2007);ZK-4044(Liang等人,Thrombosis Research,Vol.115(4):341-350,2005);WAY-140312(Crandall等人,Journal Thrombosis Haemostasis,Vol.2(8):1422-1428,2004);HP-129(fendosal)(Gils等人,Thrombosis Haemostasis,Vol.88(1):137-143,2002);T-686(Murakami等人,Japanese Journal of Pharmacology,Vol.75(3):291-294,1997);PAZ-417(aleplasinin)(Zhao等人,Cell Research,Vol.18:803-804,2008);T-2639(Miyazaki等人,Biorganic & Medicinal Chemistry Letters,Vol.18:6419-6422,2008);S-35225(Rupin等人,Thrombosis Research,Vol.122:265-270,2008);SK-216 & SK-116(Mutoh等人,Carcinogenesis,Vol.29(4):824-829,2008);2-[2-甲氧基-6-[[[3-(三氟甲基)-4-[4-[3-(三氟甲基)苯基]-1-哌嗪基]苯基]氨基]甲基]苯氧基]-5-对硝基苯甲酸(本文也称作“化合物39”;Ye等,Bioorganic & Medicinal Chemistry Letters,V0l.14(3),761-765,2004)。
其他小分子例如哌嗪和薄荷醇衍生物(Ye等人,Bioorganic & Medicinal Chemistry Letters,Vol.14(3):761-765,2004;Ye等人,Biorganic & Medicinal Chemistry Letters,Vol.13(19):3361-3365,2003),PAI-1抗体(Verbeke等人,Journal of Thrombosis and Haemostasis,Vol.2(2):289-297,2004;van Giezen等人,Thrombosis and Haemostasis,Vol.77(5):964-969,1997;和Abrahamsson等人,Thrombosis and Haemostasis,Vol.75(1):118-126,1996),以及蛋白质实际例如paionin-4(Mathiasen等人,Molecular Pharmacology,Vol.74(3):641-653,2008)在本发明特定的实施方式中也可用作抑制PAI-1表达或活性的化合物。
其他实施方式可用如下试剂,SB202190、HP-129、U0126、SP600125、bisindolylmaleimide I、粗糠柴苦素、SB431542和SIS3。他汀类试剂例如洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀可用作其他实施方式中的试剂。优选的抑制PAI-1表达或活性的化合物为tiplaxtinin、diaplasinin、化合物39和T-2639。
本发明的抑制PAI-1的表达或活性的化合物可并入多种类型的用于递送至眼部的眼科配方。使用本领域技术人员熟知的技术将所述化合物可直接递送到眼部(例如:局部眼用滴剂或软膏剂;例如植入穹隆(cul-de-sac)或植入临近巩膜或在眼内的缓释装置的药物递送海绵;眼周的、结膜的、筋膜下(sub-tenons)、前眼房内(intracameral)、玻璃体内、或小管内注射)或者全身性的递送(例如:口服;静脉内的、皮下的或肌肉内的注射;肠胃外的、皮肤或鼻部递送)。还包括本发明的PAI-1表达或活性抑制剂可配制在眼内插入物或可植入装置中。
本文公开的PAI-1表达或活性的抑制剂优选地并入局部眼用制剂用于递送至眼睛。所述化合物可以与眼科用可接受的防腐剂、表面活性剂、增稠剂、渗透促进剂、缓冲剂、氯化钠、或水组合形成一种水相的无菌的眼用混悬液或溶液。眼用溶液制剂可通过将化合物溶解在生理可接受的等渗水缓冲剂中来制备。另外,所述眼用溶液可包括眼科用可接受的表面活性剂来辅助溶解所述化合物。而且,所述眼用溶液可含有如下试剂以增加粘度,如羟甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮等等,以增强所述制剂在结膜囊内的保留。也可以使用凝胶试剂,包括但不限于结冷胶(gellan)和黄原胶。为了制备无菌的眼用软膏制剂,将活性成分与在合适载体(如矿物油、液态羊毛脂或白矿脂)中的防腐剂组合。依据用于类似眼用制剂的已发表的方法,无菌的眼用凝胶制剂可通过将所述化合物悬浮在亲水基质中制备,所述亲水基质从例如carbopol-974或诸如此类的组合中制备而成;可并入防腐剂和弹性试剂。
PAI-1表达或活性抑制剂优选地被制成局部眼用混悬液或溶液,其pH为约4-8。在局部混悬液或溶液中包含足以在IOP升高的患者中降低IOP和/或在青光眼患者中维持正常IOP水平的量的所述化合物。这样的量在本文中被称为“有效控制IOP的量”,或更简单地“有效量”。在这些制剂中通常包含0.01-5%重量/体积(“w/v%”)的量,但优选0.25-2w/v%的量的所述化合物。因此对于局部递呈,可根据有经验医师的判断,以每日1-4次将1-2滴这些制剂递送至眼睛的表面。
PAI-1表达或活性抑制剂也可与其他IOP升高或青光眼治疗剂组合使用,所述治疗剂例如但不局限于rho激酶抑制剂、β-阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳剂、5-羟色胺能激动剂和神经保护剂。
如本文使用的,“PAI-1表达或活性抑制剂”包括这类调节剂及其药学可接受的盐。PAI-1表达或活性抑制剂的药学可接受的盐是保留PAI-1表达或活性抑制的活性并被人体所接受的盐。盐可以是酸式盐或碱式盐,因为本文的试剂具有氨基取代或羧基取代。与如下所述酸制备盐:醋酸、苯甲酸、桂皮酸、柠檬酸、乙磺酸、反丁烯二酸、羟基乙酸、氢溴酸、盐酸、马来酸、丙二酸、扁桃酸、甲磺酸、硝酸、草酸、磷酸、丙酸、丙酮酸、水杨酸、琥珀酸、磺酸、酒石酸、对甲苯磺酸、三氟醋酸等等。与如下所述碱制备盐:伯胺、仲胺、叔胺、铝、铵、钙、铜、铁、锂、镁、锰、钾、钠、锌等等。
包括下列实施例来表明本发明优选的实施方式。本领域技术人员应理解所述实施例中公开的技术遵循发明人发明的代表技术得以在实施本发明时正常运作,并因此可被认为构成其实施的优选模式。然而,本领域技术人员应按照本公开理解在特定的公开的实施方式中可进行很多修改而在不背离本发明的实质和范围的情况下仍然获得同样的或相似的结果。
实施例1
可使用结合测定法或也用来确定其生物活性的功能测定法其来筛选PAI-1表达或活性抑制剂。本领域技术人员可通过使用之前描述的方法开发这些测定法。用来筛选PAI-1表达或活性抑制剂的其他有用的测定法在实施例2-5中显示。
特定PAI-1表达或者活性抑制剂安全降低IOP的能力可通过体内测定来评估。在一种这样的测定中,使用猕猴,用0.1%的丙美卡因进行轻度角膜麻醉后,用Alcon气压式眼压计(Pneumatonometer)测定眼内压(IOP)(Sharif等人,Journal Ocular Pharmacology & Therapeutics,Vol.17(4):305-317,2001;May等人,Journal of Pharmacology & Experimental Therapeutics,Vol.306(1):301-309,2003)。每次测量后,用1或2滴盐水清洗眼睛。测量基线IOP之后,向所选的眼睛中滴注1或2等份试样30μL的受试化合物。在1、3和6小时进行随后的IOP测定。所有动物的右眼进行激光小梁成形术来诱导高眼压。所有的左眼为正常并因此具有正常IOP。
在另一个测定中使用新西兰白兔,在用0.1%的丙对卡因进行轻微角膜麻醉后,用Mentor Classic 30气压式眼压计(Pneumatonometer)测定眼内压(IOP)。每次测量后,用1-2滴盐水清洗眼睛。在基线IOP测量之后,将一等份试样30μL的受试化合物滴注入每只动物的两只眼睛中,或者化合物滴注入一只眼睛而载体滴注入对侧的眼睛。在0.5、1、2、3、4和5小时进行随后的IOP测量。
实施例2
如前所述从死后人供体组织分离人TM细胞,定性和培养。也如Pang等人之前所述传代和定性转染的(GTM-3)细胞系(Curr.Eye Res.,Vol.13:51-63,1994)。对24孔板的TM细胞培养物进行去血清24小时,其后在无血清培养基中与TGFβ2温育另外的24小时(或如指示)。使用人PAI-1ELISA试剂盒(Imubind;American Diagnostica Inc.,Greenwich,CT)就分泌的PAI-1含量对来自经处理培养物的上清等份试样进行定量。ELISA检测潜伏的和活性PAI-1以及PAI-1复合物,最小检测限度为50pg/mL。
图1是显示TGFβ2升高小梁网细胞培养物(GTM-3)中的PAI-1含量的图。PAI-1介导的作用有助于之前观察到的、在包括TM组织的多种组织中TGFβ2介导的胞外基质材料积累。图2显示了这样的TGFβ2介导的PAI-1升高在用TGFβ2处理的细胞培养物中是持久的。因此,TGFβ2处理似乎导致TM细胞上清中PAI-1的浓度依赖方式和时间依赖方式的积累。PAI-1水平响应TGFβ2而逐渐升高,在处理后大约24小时达到恒定水平。
实施例3
转化生长因子-beta(TGFβ)调节广泛多种基因和蛋白质产物的产生,以及因此的多种细胞过程。研究显示用TGFβ2同种体对人小梁网(HTM)细胞进行离体处理导致纤溶酶原激活物抑制剂-1(PAI-1)表达的改变,PAI-1是可能促进眼部细胞外基质(ECM)累积的重要介导子。在TM区域中ECM不成比例的增生可对房水(AH)外流产生更大的阻力,并因此增加眼内压,例如在原发性开角型青光眼中所见。另外,从人POAG眼睛收集的AH中TGFβ2和PAI-1两者的水平高于非青光眼的眼睛。而且当灌注TGFβ2时,离体人眼球前段相应外流通畅的降低。
在这些研究中,如之前所述分离、定性和培养的人TM细胞(Pang等人,Curr.Eye Res.,Vol.13(1):51-63,1994)。对于这些测定,对铺板的细胞进行去血清24小时,其后在无血清培养基中与待测试剂温育另外的24小时。取来自经处理培养物的上清等份试样,使用人PAI-1 ELISA试剂盒(Imubind;American Diagnostica Inc.,Greenwich,CT)对PAI-1总含量进行定量。ELISA检测潜在的和活性PAI-1以及PAI-1复合物,最小检测限度为50pg/mL。用对活性PAI-1结合尿激酶进行定量的ELISA试剂盒(Molecular Innovations,Southfield,MI)测量细胞上清中的活性PAI-1含量。潜在和复合的PAI-1不结合尿激酶,并因此不能用此测定法进行检测。此测定法的期待检测极限为大约0.045U/mL(其中1单位等于大约1.34ng活性PAI-1)。
图3-9显示用上述方案进行的体外实验的结果。研究中GTM-3细胞的平均基线PAI-1分泌为33.9±1.5ng/mL/24h(n=233)。TGFβ2以时间依赖性和计量依赖性的方式增加GTM-3细胞上清中的PAI-1的含量。用5ng/mL的TGFβ2处理24h使PAI-1水平升高12.02±0.03倍。
通过与增加眼内压香港的因子(TGFβ2、TNFα、地塞米松)体外上调HTM细胞PAI-1的总蛋白质水平。TGFβ2也增加活性PAI-1水平(图3)。图4显示tiplaxtinin降低用TGFβ2处理的GTM-3培养物中的活性PAI-1水平。经典的(Smad-介导)和非经典的(Smad-非依赖型)信号转导通路的抑制剂显著(p<0.05)下调TGFβ2刺激的PAI-1水平。图5是显示PAI-1的合成抑制剂(T-2693)对经处理GTM-3细胞培养物上清中TGFβ2介导的总PAI-1蛋白质水平升高的作用。TGFβ2介导的经典(smad)信号传导通路的抑制剂(SB431542和SIS3)阻断人小梁网(HTM)细胞培养物中总PAI-1的体外表达(图6和7)。TGFβ2介导的非经典(smad-非依赖型)信号传导通路的抑制剂(SB202190、U0126、SP600125、bisindolylmaleimide I和粗糠柴苦素)也防止HTM细胞培养物中总PAI-1的体外表达。这些目前鉴定的信号传导通路包括p38MAPK、MEK1/2、JNK和PKCδ(图8)。
他汀类试剂处理也降低HTM细胞培养物中总PAI-1的体外表达(图9)。总体响应从试剂例如SB431542(TGFβ1型受体抑制剂;1μM)和粗糠柴苦素(PKCδ抑制剂;10μM)的完全抑制到SB202190(p38 MAPK抑制剂;100nM)、SP600125(c-Jun N端激酶抑制剂;1μM)以及多种他汀类试剂的部分抑制之间变化。
实施例4
进行研究来测量本发明化合物对胞外基质清除的作用。在存在或不存在tiplaxtinin、diaplasinin和化合物39的情况下处理人TM细胞24h。随后将细胞上清等份试样与IRDye 800RS-标记的酪蛋白(Li-Cor Biosciences)孵育2h,之后用Odyssey红外成像系统(Li-Cor Biosciences)检测积累的荧光降解产物。图10显示tiplaxtinin、diaplasinin和化合物39在来自6个不同HTM细胞系的每个上清等份试样中引发超过基线活性(未处理的)显而易见的增加。因此,用这些化合物的处理增强了小梁网细胞对基质蛋白质的降解。
实施例5
使用小鼠模型来测量本发明化合物的体内作用。向每只BALB/cJ小鼠的一个眼睛进行玻璃体内注视Ad5.CMV.hPAI-1或Ad.CMV.hTGFβ2226/228。未注射的对侧眼睛作为对照。在有知觉的动物中在选择的时间点通过回弹眼压计(TonoLab)测量IOP。通过每日局部给药(bid)在图中指示的时间框架内施用待测试剂。
图11是显示抑制PAI-1对t-PA和u-PA的抑制活性的两种化合物(tiplaxtinin和diaplasinin)的作用的实验结果的两个图。这些化合物几乎完全逆转了Adv.TGFβ2诱导的Balb/c小鼠的眼内压的增加。对于Adv.TGFβ2注射,通过预先和之后给药的PAI-1抑制剂实现IOP降低。
图12显示防止PAI-1对t-PA和u-PA的抑制活性的两种化合物(tiplaxtinin和diaplasinin)的作用的实验结果的两个图。两个试剂都降低了Ad.PAI-1诱导的Balb/cJ小鼠的眼内压的增加。
实施例6
氢氧化钠/盐酸 | 用来调pH到7.3-7.4 |
纯水 | 适量至100% |
实施例7
已经对本发明及其实施方式进行了详细的描述。然而,本发明的范围不旨在局限于说明书中所描述的任何过程、制备、物质的组成、化合物、方式、方法和/或步骤的具体实施方式。可对公开的材料产生多种修饰、替换和变体而不脱离本发明的实质和/或关键特征。因此,本领域普通技术人员从所公开的内容中容易理解,实施基本上相同的功能或者实现基本上相同的结果的后述修饰、替换和/或变体可以根据本发明那些相关的实施方式而使用。因此,下述权利要求书旨在在其范围内包括对本文公开的过程、制备、物质的组成、化合物、方式、方法和/或步骤的修饰、替换和变体。
参考文献
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Claims (19)
1.一种治疗患者的青光眼或IOP升高的方法,其包括:
对所述患者施用有效量的组合物,所述组合物包含抑制PAI-1表达或活性的试剂。
2.根据权利要求1的方法,其中所述试剂选自:
tiplaxtinin、diaplasinin、aleplasinin、fendosal、ZK-4044、WAY-140312、T-686、T-2639、S-35225、SK-216、SK-116、SB202190、U0126、HP-129、SP600125、XR5967、XR334、XR330、XR5118、化合物39、bisindolylmaleimide I、粗糠柴毒素、SB431542、SIS3、他汀类、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、PAI-1抗体、PAI-1蛋白质抑制剂、paionin-4及其组合。
3.根据权利要求2的方法,其中所述试剂选自:
aleplasinin、fendosal、T-2639、S-35225、SK-216、SK-116、SB202190、U0126、SP600125、化合物39、bisindolylmaleimide I、粗糠柴毒素、SB431542、SIS3、他汀类、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、PAI-1抗体、PAI-1蛋白质抑制剂、paionin-4及其组合。
4.根据权利要求3的方法,其中所述试剂选自:
tiplaxtinin、diaplasinin、bisindolylmaleimide I、T-2639、化合物39及其组合。
5.根据权利要求1的方法,其中所述抑制干扰PAI-1对组织纤溶酶原激活物(t-PA)或尿激酶纤溶酶原激活物(u-PA)活性的抑制。
6.权利要求1的方法,其中所述组合物还包含选自如下的化合物:
眼科用可接受的防腐剂、表面活性剂、增稠剂、渗透促进剂、凝胶剂、疏水基质、载体、缓冲剂、氯化钠、水及其组合。
7.权利要求1的方法,其还包括作为所述组合物的部分施用或者分别施用选自如下的化合物:
β阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳剂、神经保护剂、rho激酶抑制剂及其组合。
8.权利要求1的方法,其中所述组合物包含约0.01%重量/体积-约5%重量/体积的所述试剂。
9.权利要求1的方法,其中所述组合物包含约0.25%重量/体积-约2%重量/体积的所述试剂。
10.在有此需要的受试者中治疗PAI-1相关眼部病症的方法,其包括:
对所述患者施用有效量的组合物,所述组合物包含抑制PAI-1活性或表达的试剂。
11.根据权利要求10的方法,其中所述病症是眼高压或青光眼。
12.根据权利要求10的方法,其中所述试剂选自:
tiplaxtinin、diaplasinin、aleplasinin、fendosal、ZK-4044、WAY-140312、T-686、T-2639、S-35225、SK-216、SK-116、SB202190、U0126、HP-129、SP600125、XR5967、XR334、XR330、XR5118、化合物39、bisindolylmaleimideI、粗糠柴毒素、SB431542、SIS3、他汀类、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、PAI-1抗体、PAI-1蛋白质抑制剂、paionin-4及其组合。
13.根据权利要求12的方法,其中所述试剂选自:
aleplasinin、fendosal、T-2639、S-35225、SK-216、SK-116、SB202190、U0126、SP600125、化合物39、bisindolylmaleimide I、粗糠柴毒素、SB431542、SIS3、他汀类、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、PAI-1抗体、PAI-1蛋白质抑制剂、paionin-4及其组合。
14.根据权利要求13的方法,其中所述试剂选自:
tiplaxtinin、diaplasinin、bisindolylmaleimide I、T-2639、化合物39及其组合。
15.根据权利要求10的方法,其中所述抑制防止PAI-1对组织纤溶酶原激活物(t-PA)或尿激酶纤溶酶原激活物(u-PA)活性的抑制。
16.权利要求10的方法,其中所述组合物还包含选自如下的化合物:
眼科用可接受的防腐剂、表面活性剂、增稠剂、渗透促进剂、凝胶剂、疏水基质、载体、缓冲剂、氯化钠、水及其组合。
17.权利要求10的方法,其还包括作为所述组合物的部分施用或者分别施用选自如下的化合物:
β阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳剂、神经保护剂、rho激酶抑制剂及其组合。
18.权利要求10的方法,其中所述组合物包含约0.01%重量/体积-约5%重量/体积的所述试剂。
19.权利要求10的方法,其中所述组合物包含约0.25%重量/体积-约2%重量/体积的所述试剂。
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US4817608P | 2008-04-26 | 2008-04-26 | |
US61/048,176 | 2008-04-26 | ||
US12/421,456 | 2009-04-09 | ||
US12/421,456 US20090202524A1 (en) | 2007-10-31 | 2009-04-09 | Pai-1 expression and activity inhibitors for the treatment of ocular disorders |
PCT/US2009/040149 WO2009131850A2 (en) | 2008-04-26 | 2009-04-10 | Pai-1 expression and activity inhibitors for the treatment of ocular disorders |
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CN (1) | CN102046168A (zh) |
AR (1) | AR071393A1 (zh) |
CL (1) | CL2009000986A1 (zh) |
TW (1) | TW200946113A (zh) |
UY (1) | UY31786A1 (zh) |
WO (1) | WO2009131850A2 (zh) |
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ES2311986T3 (es) * | 2004-04-26 | 2009-02-16 | Alcon, Inc. | Estatinas para el tratamiento de la hipertension ocular y del glaucoma. |
WO2014126997A1 (en) | 2013-02-13 | 2014-08-21 | The Research Foundation For The State University Of New York | Glaucoma treatment |
CN112142845A (zh) | 2013-08-13 | 2020-12-29 | 赛诺菲 | 纤溶酶原激活剂抑制剂-1(pai-1)的抗体及其用途 |
JP6730701B2 (ja) * | 2013-11-14 | 2020-07-29 | 学校法人同志社 | 細胞増殖促進または細胞障害抑制による角膜内皮治療薬 |
CA3008113A1 (en) | 2015-12-24 | 2017-06-29 | The Doshisha | Drug for treating or preventing disorder caused by tgf-.beta. signals, and application thereof |
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DE4214215A1 (de) * | 1992-04-30 | 1993-11-04 | Behringwerke Ag | Verwendung von inhibitoren von plasminogenaktivatoren zur behandlung von entzuendungen |
AU771635B2 (en) * | 1999-01-05 | 2004-04-01 | American National Red Cross, The | Methods for treating conditions associated with the accumulation of excess extracellular matrix |
DK1397130T3 (da) * | 2001-06-20 | 2007-11-12 | Wyeth Corp | Substituerede indolsyrederivater som inhibitorer af plasminogenaktivatorinhibitor-1 (PAI-1) |
JP2005523928A (ja) * | 2002-04-30 | 2005-08-11 | アルコン,インコーポレイテッド | 眼内圧の低下および緑内障性網膜症/眼神経障害の処置の両方のための独特の手段としての、結合組織増殖因子(ctgf)の活性および/または発現を調節するか、阻害するか、または調整する薬剤 |
US8415364B2 (en) * | 2003-11-26 | 2013-04-09 | Duke University | Method of preventing or treating glaucoma |
ES2311986T3 (es) * | 2004-04-26 | 2009-02-16 | Alcon, Inc. | Estatinas para el tratamiento de la hipertension ocular y del glaucoma. |
WO2006040839A1 (ja) * | 2004-10-15 | 2006-04-20 | Advanced Medicine Research Institute | 眼疾患処置用点眼剤及びキット |
US7803824B2 (en) * | 2004-10-29 | 2010-09-28 | Alcon, Inc. | Use of inhibitors of Jun N-terminal kinases to treat glaucoma |
US20060094753A1 (en) * | 2004-10-29 | 2006-05-04 | Alcon, Inc. | Use of inhibitors of Jun N-terminal kinases for the treatment of glaucomatous retinopathy and ocular diseases |
JP2009533458A (ja) * | 2006-04-14 | 2009-09-17 | マサチューセッツ インスティテュート オブ テクノロジー | 神経系の可塑性を媒介する分子経路の同定および変調 |
EP2077829A2 (en) * | 2006-10-31 | 2009-07-15 | Alcon Research, Ltd. | Pai-1 binding modulators for the treatment of ocular disorders |
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- 2009-04-10 CN CN2009801185568A patent/CN102046168A/zh active Pending
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- 2009-04-10 WO PCT/US2009/040149 patent/WO2009131850A2/en active Application Filing
- 2009-04-10 KR KR1020107026494A patent/KR20100135953A/ko not_active Application Discontinuation
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2011
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BIN YE等: "Synthesis and biological evaluation of piperazine-based derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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CL2009000986A1 (es) | 2010-12-31 |
AR071393A1 (es) | 2010-06-16 |
EP2296647A2 (en) | 2011-03-23 |
US20110105574A1 (en) | 2011-05-05 |
JP2011518828A (ja) | 2011-06-30 |
WO2009131850A2 (en) | 2009-10-29 |
KR20100135953A (ko) | 2010-12-27 |
TW200946113A (en) | 2009-11-16 |
WO2009131850A3 (en) | 2010-01-07 |
US20090202524A1 (en) | 2009-08-13 |
UY31786A1 (es) | 2009-08-03 |
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