CN101505744A - 用于预防和治疗眼部病症的内皮分化基因亚家庭3(edg-3,s1p3)受体的拮抗剂 - Google Patents
用于预防和治疗眼部病症的内皮分化基因亚家庭3(edg-3,s1p3)受体的拮抗剂 Download PDFInfo
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Abstract
提供S1P3(Edg-3)受体的拮抗剂用来在涉及CTGF积累的眼部病症中下调受体信号和下游减少产生的结缔组织生长因子产物的方法中减弱Smad信号传导。涉及不适当CTGF积累的眼部病症包括例如高眼压、青光眼、青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变和眼创伤愈合。通过施用本发明的拮抗剂治疗这些病症。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119要求2006年7月25日提交的美国临时专利申请序号60/833,080的优先权,其全部内容通过引用并入本文。
本发明的技术领域
本发明涉及用于减弱内皮分化基因亚家族3受体的组成物的领域,所述减弱用来在涉及CTGF积累的眼部病症中下调受体信号传导和结缔组织生长因子(CTGF)产生的下游减少。
发明背景
大多数眼部病症与包括细胞增殖、存活、迁移、分化和血管生成的细胞过程有关。CTGF被认为是作为这些细胞过程中的中心中介体的一种分泌的细胞因子。尤其是,已知CTGF通过I型胶原蛋白和纤连蛋白的储存增加来增加细胞外基质产生。暗示CTGF的过量表达是例如硬皮病、纤维增生性疾病和细胞外基质成分过量积累的瘢痕的病况中的主要致病因素。
在小梁网(TM)区域中的细胞外基质的过量积累是某些形式青光眼的标志;认为这种增加导致对水流出阻力的增加以及因此提高的眼内压(IOP)。属于Fleenor等人在2003年11月13日作为WO03/092584公布并转让给Alcon,Inc.的国际专利申请序号PCT/US2003/012521描述了相对正常TM细胞,在青光眼的TM细胞中CTGF mRNA的存在升高。于是,认为CTGF在小梁网细胞的细胞外基质产生中起作用
小梁网(TM)是一种复合组织,其包括内皮细胞、结缔组织和位于角膜和虹膜之间夹角的提供维持正常IOP所需的正常阻力的细胞外基质。需要适当的IOP来维持眼的形状并且提供压力梯度从而允许眼房水流进入无血管的角膜和晶状体。通常在青光眼中出现的过高IOP,对视神经具有有害作用,引起视网膜神经节细胞和轴突的损失,并导致渐进的视觉丧失而且如不治疗可导致失明。青光眼是世界范围内失明的首要原因之一。
原发性青光眼起因于具有解剖学、生物化学或生理基础的眼房水流的扰乱。继发性青光眼发生是眼睛的损伤或创伤或先在疾病的结果。原发性开角型青光眼(POAG),也就是所知的慢性或简单型青光眼,占美国所有原发性青光眼的90%。POAG的特征为导致对眼的流体排水的异常高阻力的TM病理改变。这种阻力的结果是IOP的增加。
已知例如泼尼松、地塞米松和氢化可的松的某些药物通过提高IOP诱导青光眼。此外,施用方式似乎影响IOP。例如,地塞米松的眼内施用比全身性施用导致IOP的更强的升高。由施用类固醇导致的青光眼被称为类固醇诱导的青光眼。
目前抗青光眼的治疗通过使用药物治疗来压制眼房水形成或促进水流出来降低IOP,也可通过手术程序,例如激光小梁成形术、或小梁切除术来改善水排出。药物性抗青光眼方法已经显现多种不希望的副作用。例如,缩瞳剂(如匹鲁卡品)可引起视觉模糊和其他负面的局部副作用。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。此外,已将β-阻断剂与肺部副作用联系起来是由于其对肺部组织中的β-2受体的作用。Alpha2-激动剂可引起心动过速、心律不齐和高血压。这类负面的副作用可导致患者依从性的降低或治疗终止。
公布于2005年10月20日属于Fleenor等人的美国公布专利申请序号2005/0234075(将其通过引用并入本文),提供了GSK-3和CDK抑制剂对在人小梁网细胞中基础的以及TGFβ2诱导的CTGF的表达具有抑制活性。
黄斑变性是在中央视网膜的部分(称为黄斑)的光受体的丢失,黄斑负责高敏锐视觉。黄斑的变性与细胞外基质组分在视网膜色素上皮与脉管脉络膜之间的膜上的异常沉积有关。这种碎片样物质称为脉络膜小疣。通过眼底检查观察到脉络膜小疣。正常眼睛可具有无脉络膜小疣的黄斑,然而在视网膜周边有丰富的脉络膜小疣。在黄斑视觉无任何损失的情况下,黄斑上柔软脉络膜小疣的存在被认为是早期AMD。
除其他眼部病症之外,在黄斑变性中通常还发生脉络膜新生血管形成,并其与脉络膜内皮细胞增殖、细胞外基质过量产生以及维管亚视网膜形成有关。视网膜色素上皮细胞增殖和血管生成因子的产生似乎影响脉络膜新生血管形成。
糖尿病性视网膜病变是一种在糖尿病中由于毛细血管基底膜增厚以及毛细血管的周细胞和内皮细胞之间缺乏接触而发展成的眼部病症。周细胞的丢失增加毛细血管的渗漏并引起血-视网膜屏障的瓦解。
增殖性玻璃体视网膜病变与玻璃体膜中和视网膜表面上的细胞性膜和纤维性膜的细胞增殖有关。视网膜色素上皮细胞增殖和迁移常见于此眼部病症中。与增殖性玻璃体视网膜病变有关的膜包含细胞外基质组分,例如I、II和IV型胶原蛋白以及纤连蛋白,并逐渐地变成纤维变性(fibrotic)。
创伤愈合病症可引起严重的眼组织损害,其通过炎性细胞的激活、生长因子和细胞因子释放、眼细胞的增殖和分化、毛细血管渗透性的增加、基底膜基质组成物的改变、细胞外基质沉积(deposition)的增加、纤维化、新生血管形成和组织重塑。
鉴于如上所述的眼部病症的重要性,尤其是小梁网的病理损害和由于细胞外基质过量产生造成的损害,需要有一种治疗这些眼部病症的改良的方法来解决其进展的潜在原因。
本文所有缩写包括:
AC 腺苷酸环化酶
AP-1 激活蛋白1转录因子
CTGF 结缔组织生长因子
DG 二酰基甘油
Edg3 内皮分化基因亚家族3受体,见S1P3
ERK 细胞外信号调控激酶
G12/13,Gq/11,Gi 鸟嘌呤核苷酸结合蛋白亚类
IOP 眼内压
IP3 三磷酸肌醇
LPA 溶血磷脂酸
PAI-1 纤溶酶原激活物抑制剂1
PKC 蛋白激酶C
PLC 磷脂酶C
PLD 磷脂酶D
Raf 蛋白激酶raf-1
Ras 小GTP-结合蛋白
Rho 小GTP-结合蛋白
S1P 鞘氨醇-1-磷酸
S1P3或S1PR3 鞘氨醇-1-磷酸受体3
Smad-1、-2、-3 受体调节的Smad转录因子
Smad-4 公共伴侣(common partner,Co-)Smad转录因子
TGFβ 转化生长因子β
TGFβR、TβRI、TβRII转化生长因子β受体、I型转化生长因子β受体、II型转化生长因子β受体
本发明概述
本发明探讨本领域如上所述的问题并且提供了一种通过提供S1P-3受体的拮抗剂用于减弱受试者眼内的Smad信号传导的方法。减弱受试者眼内的Smad信号传导的方法包括向受试者施用一种组成物,该组合物含有有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐、以及药物学可接受的载体。从而减弱受试者眼内的Smad信号传导。受试者可能具有导致不适当的结缔组织生长因子积累的Smad信号传导相关眼部病症或处于发展成这类眼部病症的危险中。Smad信号传导相关眼部病症可以是例如高眼压、青光眼、青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变或眼创伤愈合。
内皮分化基因亚家族3受体的拮抗剂降低天然配体与该受体的结合。所述拮抗剂包括该受体的天然配体的类似物——鞘氨醇-1-磷酸。该拮抗剂可为取代的噻唑烷、取代的噻嗪烷(thiazinane)、或具有如下所述结构III的S1P类似物。所述拮抗剂可为例如苏拉明的多磺化萘脲、对S1P3受体具有结合亲和性和特异性的抗体、其生物活性片段、或对所述受体具有结合亲和性和特异性的肽或拟肽。
本发明的另一个实施方案是一种治疗与有此需要的受试者体内的不适当的结缔组织生长因子积累关联的Smad信号传导相关眼部病症的方法。所述方法包括向受试者施用一种组成物,所述组成物包含有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐,以及药物学可接受的载体。从而治疗Smad信号传导相关眼部病症。
在本发明的一个实施方案中,提供一种在受试者中治疗青光眼的方法。所述方法包括向受试者施用一种组成物,该组成物包含有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐,以及药物学可接受的载体,其中青光眼从而被治疗。
在本发明另一个实施方案中,提供了一种治疗受试者中的青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变或眼创伤愈合的方法。所述方法包括向受试者施用一种组成物,该组成物包含有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐,以及药物学可接受的载体。青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变或眼创伤愈合从而被治疗。
附图简述
图1提供了显示信号转导的示意图,其包括S1P和Smad,并包括TGF-β和Smad;S1P-1、-2、-3、S1P受体;TGFβR、1型和2型TGF-β受体(改编自Xin等人,JBG,Vol.279(34):35255-35262,2004;Blom,等人,Matrix Biology,Vol.21:473-482,2002;Takuwa,Y.,Biochim Biophys Acta.,Vol.1582:112-120,2002;Pyne等人,BiochemJ,Vol.349:385-402,2000;和Xu等人,Acta PharmacolSin.,Vol.25:849-854,2004)。
图2A和图2B。存在多种量的内源Edg受体激动剂S1P(图2A)或存在多种量的S1P结构类似物FTY720(图2B)的情况下,使用(空圆圈)或不使用(实圆圈)Edg3受体亚型拮抗剂CAY10444来处理人小梁网细胞培养物。24小时之后,是如实施例2中所述通过对来自的处理后培养物的上清等份试样的ELISA确定分泌的PAI-1蛋白的水平。
发明详述
S1P-3(Edg-3)受体属于LPA或S1P作为其内源配体的G蛋白偶联受体家族。LPA是Edg-2、-4、和-7受体的配体而S1P是Edg-1、-3、-5、-6、和-8受体的配体。国际药理学联合会已经将Edg受体重新命名为S1P(Chun等人,Pharmacol Rev,Vol.54:265-269,2002)。因此,如本文所用,术语“Edg受体”是术语“S1P受体”的同义词。图1提供了S1P受体与调节靶标Smad之间以及TGFβ受体和相同的调节靶标Smad之间的信号转导关系的示意图。Smad通过磷酸化激活并且与Smad4形成复合物以产生一个异源复合物,所述异源复合物进入核内,其中该复合物与其他转录因子一起激活基因转录,例如编码CTGF的基因的转录。
较之于“正常”眼睛,从青光型人眼中收集到的眼房水中发现显著更高水平的TGFβ2同种型(Tripathi等人,Exp Eye Res,Vol.59(6):723-727,1994;Inatani等人,Graefes Arch Clin ExpOphthalmol,Vol.239(2):109-113,2001;Picht等人,Graefes ArchClin Exp Ophthalmol,Vol.239(3):199-207,2001;Ochiai等人,JpnJ Ophthalmol,Vol.46(3):249-253,2002)。此外,在灌注人眼前段模型中TGFβ2可以激起IOP的大幅增加(Fleenor等人,InvestOphthalmol Vis Sci,Vol.47(1):226-234,2006)。因此,TGFβ,尤其是TGFβ2,似乎在IOP相关病变如青光眼中起致病作用。
S1P-3受体似乎在肾系膜细胞中激活Smad信号传导通路(Xin等人,Br J Pharmacol,Vol.147:164-174,2006)。另外,已知Smad蛋白介导通过TGF亚家族成员激活的标准信号通路,包括TGF-β信号通路(由图1所示)。因此,S1P-3诱导的Smad蛋白信号激活似乎模拟了一些已知受TGFβ调控的细胞反应。此外,已知TGFβ和S1P都增强CTGF的表达(Xin等人,2004 Id.,Katsuma et al.,FEBS Letters,Vol.579:2576-2582,2005),CTGF似乎是在青光眼过程中起重要作用的一个蛋白(属于Fleenor等人在2003年11月13日作为WO03/092584公布并转让给Alcon,Inc.的国际专利申请序号PCT/US2003/012521)。
因为TGFβ在组织中既有正面作用又有反面作用,所以希望得到TGFβ/S1P3信号通路的选择性调制。正面作用包括,例如,TGFβ作为抗炎剂、作为免疫抑制剂、以及作为T细胞迁移和归巢的促进剂。本文提供了这种选择性调制。
本发明人在本文提供了眼部S1P3受体的拮抗剂,所述拮抗剂导致经由Smad受体的信号传导降低,由此降低下游的CTGF积累。本文所提供的Smad下游通路的调制导致TGFβ信号传导的负面的降低,同时保留TGFβ的正面信号传导效用基本上不受影响。本发明的另一个实施方案提供了拮抗S1P3受体结合从而干扰S1P3下游信号传导级联,并尤其干扰Smad信号传导的方法,所述方法用于治疗其中Smad蛋白信号传导导致不适当的结缔组织生长因子积累的眼部病症,。
内皮分化基因亚家族3受体(EDG-3,S1P-3)的拮抗剂:S1P-3受体的拮抗剂包括减弱S1P-3受体和其天然配体S1P之间的结合亲和力或特异性的试剂。所述拮抗剂可以是S1P类似物。拮抗剂可以是取代的噻唑烷,尤其是烷基取代的噻唑烷或芳基烷基取代的噻唑烷;取代的噻嗪烷,尤其是烷基取代的噻嗪烷;多磺化萘脲,例如苏拉明(最常见可得的是六钠盐;或具有如下所述结构III的S1P类似物;对于S1P3受体具有结合特异性和亲和力的抗体、其生物活性抗体片段、肽或拟肽;或拮抗剂的药物学可接受的盐。本文所述拮抗剂可以是外消旋混合物、非对映体或对映体。
“拮抗剂的药物学可接受的盐”是保持S1P3受体拮抗活性并为人体可接受的拮抗剂的盐。因为本文的拮抗剂可具有氨基或羧基取代,所以盐可以是酸性盐或碱性盐。
取代的噻唑烷具有结构I:
其中R1为C6-C13烷基、或取代为C5-C9烷基的烷基取代的芳基。在本发明的一个实施方案中,所述拮抗剂具有结构I,其中R1为C10烷基或C11烷基,(2-烷基噻唑烷-4-羧酸,其中烷基为C10或C11)。当R1为C11烷基,所述拮抗剂为通过商业途径从Cayman Chemical(AnnArbor,Michigan)获得的CAY10444。在本发明另一个实施方案中,所述拮抗剂具有结构I,其中R1是烷基-取代的苯基,并且苯环上的取代为m-或p-C7-烷基,也就是(2-(m-或p-庚基苯基)噻唑烷-4-羧酸)。
本发明一个实施方案中,S1P3的拮抗剂具有结构II:
其中R2为C9-C13烷基。
本发明另一个实施方案中,S1P3的拮抗剂具有结构III:
其中R3为o-或m-C5-C8烷基;并且R4是磷酸脂、磷酸脂类似物、膦酸酯或硫酸酯。本文所用“磷酸类似物”包括术语例如硫代磷酸脂、二硫代磷酸脂、硒代磷酸脂、二硒代磷酸脂、phosphoro-anilothioates、磷酸酰苯胺、氨基磷酸脂或磷酸硼
2005年10月6日公布的属于Lynch等人的美国专利申请公布号2005/0222422(通过引用并入本文)以及Koide等人JMedChem,Vol.45:4629-4638,2002描述了S1P3信号传导中有活性的其他化合物,。
用于鉴定另外的S1P3受体拮抗剂的测定法使用竞争性结合测定,所述测定包括组合候选拮抗剂、S1P、S1P3受体和对活化的S1P3受体具有活性的激酶,并测量所得磷酸化S1P3受体的量。将结果与在不存在候选拮抗剂的相同试验中所获得的磷酸化S1P3受体的量相比较。当磷酸化S1P3受体水平低于候选拮抗剂不存在时的水平,候选拮抗剂具有拮抗活性。进一步的测定包括如下测定:通过候选拮抗剂抑制受体特异性的抗体结合、通过候选拮抗剂减少CTGF mRNA的积累、或通过候选拮抗剂减少CTGF蛋白的积累。先前通过引用并入本文的2005年10月6日公布的属于Lynch等人的美国专利申请公布号2005/0222422,描述了用来测量S1P模拟物对人的S1P受体的S1P活性的GTP结合测定。
使用本领域所知的方法合成取代的噻唑烷和取代的噻嗪烷,例如Koide等人描述的方法(J Med Chem,Vo1.45:4629-4638,2002)。先前通过引用并入本文的2005年10月6日公布的属于Lynch等人的美国专利申请公布号2005/0222422描述了具有结构III的S1P类似物的合成。
市场上可买到对于S1P3受体具有结合特异性和亲和性的抗体,例如鼠的单克隆抗体可从GENETEX,Inc.(Catalog Number GTX12254,San Antonio,TX)获得,针对鞘脂受体Bdg3/S1P3的兔多克隆抗体可从Novus Biologics Inc.(Catalog Number NLS 1031,Littleton,CO)获得,而且EDG-3CT抗体可从Exalpha Biologicals,Inc.(Watertown,MA)获得。EDG-3CT对于人S1P3受体的独特的C端肽具有结合亲和性和特异性。
也通过观察在眼部病症中的改善推断人和哺乳动物中S1P-3受体的拮抗作用以及产生的对CTGF积累的抑制作用。例如在年龄相关的黄斑变性中,视觉丧失的减缓和逆转表明了CTGF积累的抑制作用,以及在青光眼患者中,在具有发展为青光眼的危险的受试者中眼内压的降低和症状发生的延迟或预防表明了CTGF积累的抑制作用。
本发明的拮抗剂可与用于治疗CTGF积累或活性不适当的眼部病症的其他试剂组合使用,例如先前通过引用并入本文的2005年10月20日公布的属于Fleenor等人的美国专利申请号2005/0234075描述的试剂。
施用模式;使用本领域技术人员熟知的技术将拮抗剂直接递送到眼部(例如:局部的眼部滴剂或软膏剂;在穹隆(cul-de-sac)中或植入临近巩膜(穿巩膜)或在眼内的缓释装置;眼周的、结膜的、筋膜下(sub-Tenons)、前眼房内(intracameral)、玻璃体内、视网膜下、眼球后的、或小管内注射)或全身性的递送(例如:口服;静脉内的、皮下的或肌肉内的注射;肠胃外的、真皮递送)。还包括本发明的拮抗剂可配制在一个定位装置中例如视网膜丸剂、眼内插入物、导管、栓剂或含有多空的、非多孔的或凝胶状的材料的植入装置。前眼房内注射可通过角膜进入眼前房从而允许实际到达小梁网。小管内注射可进入巩膜静脉窦的排水静脉收集通道或进入巩膜静脉窦。
受试者;需要治疗眼部病症或处于发展为眼部病症的危险中的受试者是具有与CTGF不适当积累的Smad激活相关的病况或处于具有所述病况的危险中的人或其他哺乳动物。这种眼部病症包括,例如,高眼压、青光眼、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变、眼创伤愈合、以及具过度瘢痕、内皮细胞增殖或纤维化增殖的病况。与这些病症相关的眼部结构包括例如视网膜、脉络膜、晶状体、角膜、小梁网、视杆、视锥、神经节、黄斑、虹膜、巩膜、眼房、玻璃体小室、睫状体、视神经盘、视神经乳头或中央凹。
制剂和剂量:药物制剂包括拮抗剂、或其盐,如本文所述多至重量99%的生理可接受的眼部的载体介质混合,如水、缓冲剂、盐水、甘氨酸、透明质酸、甘露醇及诸如此类。本发明各方面包括的可能制剂的实例如下:
化合物 | 以重量%计量 |
S1P-3受体拮抗剂 | 多至99;0.1-99;0.1-50;0.5-10.0;0.01-5.0;0.01-2.0;0.02-2.0;0.1-1.0;0.5-2.0 |
羟丙基甲基纤维素 | 0.5 |
氯化钠 | .8 |
苯扎氯胺 | 0.01 |
EDTA | 0.01 |
NaOH/HC1 | 适量pH7.4 |
纯水 | 适量100mL |
化合物 | 以重量%计量 |
S1P-3受体拮抗剂 | 多至99;0.1-99;0.1-50;0.5-10.0;0.01-5.0;0.01-2.0;0.02-2.0;0.1-1.0;0.5-2.0;0.00005-0.5;0.0003-0.3;0.0005-0.03;0.001 |
磷酸缓冲盐水 | 1.0 |
苯扎氯胺 | 0.01 |
聚山梨醇酯80 | 0.5 |
纯水 | 适量至100% |
化合物 | 以重量%计量 |
S1P-3受体拮抗剂 | 多至99;0.1-99;0.1-50;0.5-10.0;0.01-5.0;0.01-2.0;0.02-2.0;0.1-1.0;0.5-2.0;0.001 |
磷酸二氢钠 | 0.05 |
磷酸氢二钠(无水) | 0.15 |
氯化钠 | 0.75 |
二钠EDTA | 0.05 |
聚氧乙烯蓖麻油 | 0.1 |
苯扎氯胺 | 0.01 |
HCl和/或NaOH | pH7.3-7.4 |
纯水 | 适量至100% |
化合物 | 以重量%计量 |
S1P-3受体拮抗剂 | 多至99;0.1-99;0.1-50;0.5-10.0;0.01-5.0;0.01-2.0;0.02-2.0;0.1-1.0;0.5-2.0;0.0005 |
磷酸缓冲盐水 | 1.0 |
羟丙基-β-环糊精 | 4.0 |
纯水 | 适量至100% |
在另外的一个实施方案中,眼用的组合物经配置以提供拮抗剂的眼内浓度约0.1-100纳摩尔(nM)或,在另外的一个实施方案中是1-10nM的拮抗剂。依据熟练的临床医师的常规的酌情决定将局部组合物每日1-4次递送到眼部表面。制剂的pH应为4-9或4.5-7.4。全身性制剂可含有约10-1000mg的拮抗剂。
“有效量”指能够干扰S1P-3受体与Smad之间的结合的S1P-3受体拮抗剂的量。此干扰导致Smad活性的降低、CTGF基因转录的降低、CTGF蛋白积累的降低以及由此产生的受试者中眼部病症的症状减轻。此干扰延迟或预防处于发展成本文所述的眼部病症的危险中的受试者中症状的发生。制剂的有效量依赖于如受试者的年龄、种族和性别或例如眼部状况的严重程度的因素。在一个实施方案中,所述拮抗剂以治疗剂量局部递送到眼部并到达小梁网、视网膜或视神经头从而改善眼部病症的进展。
可接受的载体:眼用可接受的载体指那些最多引起极少至没有眼部刺激、如果需要可提供合适的保护、并以均质剂量递送本发明的一种或多种S1P-3拮抗剂的载体。对于眼部递送,S1P-3拮抗剂可以与眼科用可接受的防腐剂、共溶剂、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拮抗剂溶解在生理可接受的等渗水缓冲剂中来制备。另外,眼用溶液可包括眼科用可接受的表面活性剂来辅助溶解拮抗剂。粘度生成试剂,如羟甲基纤维素、羟乙基纤维素、甲基纤维素、聚乙烯吡咯烷酮或诸如此类,可添加到本发明的组合物中以增强化合物的保留。
为了制备无菌的眼用软膏制剂,将S1P-3拮抗剂与在合适载体(如矿物油、液态羊毛脂或白矿脂)中的防腐剂组合。依据用于其他眼用制剂的为本领域所知的方法,无菌的眼用凝胶制剂可通过将S1P-3拮抗剂悬浮在亲水基质中制备,所述亲水基质从例如-940(BF Goodrich,Charlotte,NC)或诸如此类的组合中制备而成。例如(Alcon Laboratories,Inc.,Fort Worth,TX)可用于眼内注射。在S1P-3拮抗剂在眼中渗透性较低的情况下,本发明的其他组合物含有渗透促进剂如乳浮(cremophor)和80(聚氧乙烯山梨醇酐单月硅酸酯,Sigma Aldrich,St.Louis,MO)。
试剂盒:本发明的实施方案提供了包括用于减弱细胞内的S1P3受体信号传导的拮抗剂的试剂盒。所述试剂盒包括含本发明拮抗剂的密封的一个或多个容器、药物学可接受的载体以及可选的印刷使用说明。
实施例1
对S1P-刺激的CTGF基因表达的抑制
Edg3受体拮抗作用对培养的人小梁网细胞中CTGF基因表达的作用可如下确定。用或不用刺激性量的鞘氨醇-1-磷酸(S1P)以及用或不用Edg3受体拮抗剂对转化的或非转化的人TM细胞培养物处理一定的时间(Pang等人,Curr Eye Res,Vol.13:51-63,1994;Steely等人,Invest Ophthalmol Vis Sci,Vol.33:2242-2250,1992;Wilson等人,Curr Eye Res,Vol.12:783-793,1993;Stamer等人,Curr Eye Res,Vol.14:611-617,1995)。用必需稀释度的载体处理另外的培养物以用作对照。使用Qiagen RNeasy 96系统依照制造商的使用说明(Qiagen)从TM细胞中分离总RNA。
基本上如先前所述(Shepard等人,IOVS,Vol.42:3173,2001)使用ABI 7700 Sequence Detection System(AppliedBiosystems),通过定量实时RT-PCR(QRT-PCR)验证细胞处理后的CTGF的差异表达。如属于Fleenor等人于2004年10月8日提交的USSN10/510,585、于2005年10月20日公布的美国公布专利申请号20050234075所述,使用Primer Express软件(Applied Biosystems)设计用于CTGF扩增的引物以退火到Genbank收录号#NM001901.1的邻近的外显子上,从而产生76-bp的扩增子。CTGF的扩增相对于18S核糖体RNA表达进行标准化,其中使用如属于Fleenor等人的美国公布专利申请号20050234075所述(同上)针对18SrRNA基因(GenBank收录号#X03205)设计的引物来产生69-bp扩增子。CTGF QRT-PCR与18S引物/探针集一起以50ul终体积进行多重执行,所述终体积由40nM18S或900nM CTGF引物;100nM18S探针或100nM CTGF;5ul RNA;1XMultiscribe and RNase InhibitorMix(ABI);以及1X Universal Mix(ABI)组成。热循环条件由48℃ 30min和95℃ 10min,随后40个循环的95℃ 15sec和60℃ 1min构成。用SDS软件1.9.1版本(Applied Biosystems)和MS Excel 2002(Microsoft)进行数据分析。使用PE Biosystems User Bulletin #2中所述的ΔΔCt法进行相对RNA浓度的定量。用四份QRT-PCR测定的平均±SEM表示扩增产物的水平。用SDS软件1.9.1版本(Applied Biosystems)和MS Excel97(Microsoft)进行数据分析。
实施例2
对S1P-刺激的细胞外基质相关蛋白表达中的变化的抑制
Edg3受体拮抗剂对培养的人小梁网细胞的细胞外基质相关蛋白表达的作用如下确定。将人TM细胞培养物分成重复的和/或实验组和/或对照组,向其中加入对照溶液或实验溶液,所述溶液含有稀释载体(作为对照)和/或S1P(作为刺激剂)和/或Edg3受体拮抗剂。随后通过标准酶联免疫吸附测定(ELISA)测试每个细胞培养物组中细胞外基质相关蛋白的水平,例如纤连蛋白、纤溶酶原激活物抑制剂I(PAI-1)、胶原蛋白、肌原纤蛋白、玻连蛋白、层纤连蛋白、血小板反应蛋白I、蛋白聚糖或整合素。此测定为本领域技术人员所熟知并且是灵敏的免疫测定,其使用连接至抗体或抗原的酶作为检测特定蛋白的标签。通过这些方法,在组之间比较不同的细胞外基质相关蛋白的水平用来确定试验溶液的作用。
图2A和2B显示了Edg3受体对处理后的人TM细胞培养物而来的上清中PAI-1的水平的拮抗作用的一个实例。对于这些研究,在不同量的内源Edg受体激动剂S1P存在时和/或在不同量的一种S1P结构类似物FTY720存在时,用或不用Edg3受体亚型拮抗剂CAY10444处理人TM细胞培养物。24小时后,随后通过来自处理后的培养物的上清等量试样的ELISA确定分泌的PAI-1蛋白水平。从这些数据表明CAY10444强有力地和有效地拮抗了两种激动剂的作用(数据代表平均和SEM)。
本文所引用的文献以提供了对于本文所述那些补充的示例性的程序性或其它细节的程度,通过特定地引用并入本文。
本领域的技术人员依照本公开,会理解可产生本文所公开的实施方案的明显修饰而不脱离本发明的精神和范围。依据本公开无需过度实验可进行或执行本文所公开的全部实施方案。本公开和其等价的实施方案陈述了本发明的全部范围。说明书不应该解释为过度使本发明给予的保护的全部范围狭窄。
除非另外指明,如本文所用的属于“一”和“一个”意为“一个”“至少一个”或“一个或多个”。
Claims (35)
1.一种减弱受试者眼内的Smad信号传导的方法,包括:
向受试者施用一种组合物,该组合物包含:
有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐;以及
药物学可接受的载体;
其中所述受试者眼内的Smad信号传导从而被减弱。
2.权利要求1的方法,其中所述受试者患有具有不适当的结缔组织生长因子积累的Smad信号传导相关眼部病症。
3.权利要求1的方法,其中受试者处于发展成具有不适当的结缔组织生长因子积累的Smad信号传导相关眼部病症的危险。
4.权利要求2的方法,其中所述Smad信号传导相关眼部病症是高眼压、青光眼、青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变或眼创伤愈合。
5.权利要求1的方法,其中所述拮抗剂是鞘氨醇-1-磷酸类似物。
6.权利要求1的方法,其中所述拮抗剂是取代的噻唑烷。
7.权利要求1的方法,其中所述拮抗剂是取代的噻嗪烷。
8.权利要求1的方法,其中所述拮抗剂具有结构I:
其中R1是C6-C13烷基、或烷基取代的芳基,其中芳基取代是C5-C9烷基。
9.权利要求8的方法,其中R1是C10或C11烷基。
10.权利要求8的方法,其中R1是烷基取代的苯基并且取代是m-或p-C7-烷基。
12.权利要求1的方法,其中所述拮抗剂是多磺化萘脲。
14.权利要求1的方法,其中所述拮抗剂是对所述受体具有结合亲和性和特异性的抗体或其生物活性片段。
15.权利要求1的方法,其中所述拮抗剂是对所述受体具有结合亲和性和特异性的肽或拟肽。
16.权利要求1的方法,其中通过局部、前眼房内、玻璃体内、经巩膜或植入途径施用所述组合物。
17.权利要求1的方法,其中所述组合物中的所述拮抗剂的浓度为0.01%-2%。
18.一种在有此治疗的受试者中治疗具有不适当的结缔组织生长因子积累的Smad信号传导相关眼部病症的方法,包括:
向受试者施用一种组合物,该组合物包含:
有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐;以及
药物学可接受的载体;
其中所述Smad信号传导相关眼部病症从而被治疗。
19.权利要求18的方法,其中所述受试者患有高眼压或青光眼。
20.权利要求18的方法,其中所述受试者处于发展成高眼压或青光眼的危险。
21.权利要求18的方法,其中所述拮抗剂是鞘氨醇-1-磷酸类似物。
22.权利要求18的方法,其中所述拮抗剂是取代的噻唑烷。
23.权利要求18的方法,其中所述拮抗剂是取代的噻嗪烷。
25.权利要求24的方法,其中R1是C10或C11烷基。
26.权利要求24的方法,其中R1是烷基取代的苯基并且取代是m-或p-C7-烷基。
27.权利要求18的方法,其中所述拮抗剂具有结构II:
其中R2是C9-C13烷基。
28.权利要求18的方法,其中所述拮抗剂是多磺化萘脲。
30.权利要求18的方法,其中所述拮抗剂是对所述受体具有结合亲和性和特异性的抗体或其生物活性片段。
31.权利要求18的方法,其中所述拮抗剂是对所述受体具有结合亲和性和特异性的肽或拟肽。
32.权利要求18的方法,其中通过局部、前眼房内、玻璃体内、经巩膜或植入途径施用所述组合物。
33.权利要求18的方法,其中所述组合物中的所述拮抗剂的浓度为0.01%-2%。
34.一种在受试者中治疗青光眼的方法,包括:
向受试者施用一种组合物,该组合物包含:
有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐;以及
药物学可接受的载体;
其中青光眼从而被治疗。
35.一种在受试者中治疗青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变或眼创伤愈合的方法,包括:
向受试者施用一种组合物,该组合物包含:
有效量的内皮分化基因亚家族3受体的拮抗剂或其药物学可接受的盐;以及
药物学可接受的载体;
其中青光眼性视网膜病变、视神经病变、黄斑变性、糖尿病性视网膜病变、脉络膜新生血管形成、增殖性玻璃体视网膜病变或眼创伤愈合从而被治疗。
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