CN101330914A - 使用alk5调节剂控制眼内压 - Google Patents
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Abstract
公开了一种治疗青光眼和控制眼内压的包含有效量ALK5受体活性选择性调节剂的眼用药物组合物。还公开了一种治疗青光眼和控制眼内压的方法,包括向患者受影响的眼睛应用包含ALK5受体活性选择性调节剂的治疗有效量的药物组合物。
Description
在美国专利商标局用于申请美国专利特许证
本申请依据35U.S.C.§119要求2006年12月16日提交的美国临时专利申请号60/751,130的优先权,在此全部引入作为参考。
技术领域
本发明主要涉及对青光眼的治疗,和更特别涉及选择性调节活化素受体样激酶5(ALK5、或1型TGF-β受体)从而降低眼内压,例如与青光眼有关,的药物。
背景技术
眼病青光眼的特征在于由于不可逆的破坏视神经导致视觉功能的永久损失。青光眼的几种形式上或功能上的不同类型的典型特征在于眼内压(IOP)的不良升高,其被认为引起相关疾病的病理过程。连续升高的眼内压与视网膜的渐进损坏和视觉功能的损失有关。有时,眼高压,一种眼内压被升高的状态,可以在不显示出视觉功能的明显损失的情况下存在。然而,具有眼高压的患者被认为是最终发展为与青光眼相关的视觉损失的高风险者。因此,降低眼内压是对于治疗青光眼病人和具有眼高压的病人的可能的一个目标,用于降低潜在的,或严重的青光眼视网膜病。不幸地是,当使用现有的青光眼疗法治疗时许多个体没有很好的应答。
已知为压力正常或低压性青光眼的患者具有相对低的眼内压,然而也呈现出青光眼视野损失。这些患者能受益于降低和控制眼内压的药物,因为早期检测和迅速治疗青光眼能降低和延缓视觉功能损失。传统的已经证明对降低眼内压有效的治疗药物包括减少房水产生的药物和增加流出量的药物两种。这些药物通常由两种途径中的一种给予;局部地直接应用到眼上,或口服。然而,这些药物中的许多具有相应的使它们变得不适合作为眼睛治疗药物的副作用。
转化生长因子-β(TGF-β)族的细胞因子包括调节多种基因产物产生的多功能蛋白质,并从而控制多种细胞代谢过程。例如,其中TGF-β族成员涉及炎症、伤口愈合、细胞外基质累积、骨形成、组织发育、细胞分化和肿瘤进展。[Barnard et al.,Biochim BiophysActa.1990;Vol.1032:79-87;Spornet al.,J Cell Biol.,1992;Vol.119:1017-1021;Yingling et al.,Nature Reviews,2004;Vol.3:1011-1022;Janssens et al.,Endocr Rev.,2005;(在印刷前的电子出版)]。迄今为止已经识别了三种哺乳动物亚型:TGF-β1、TGF-β2和TGF-β3,并且尽管是由不同基因编码的,但这些亚型是结构近似的。[Massague J.,Annu Rev Cell Biol.,1990;Vol.6:597-641]
在从患有一种西方患者中最常见类型的青光眼原发性开角型青光眼(POAG)的人眼中采集的房水(AH)中,各研究组已经报导与正常眼相比TGF-β2亚型有显著的高水平。[Tripathi et al.,Exp EyeRes.,1994;Vol.59:723-727;Inatani et al.,Graefes Arch ClinExp Ophthalmol.,2001;Vol.239:109-113;Picht et al.,Graefes Arch Clin Exp Ophtha lmol.,2001;Vol.239:199-207;Ochiai et al.,Jpn J Ophthalmol.,2002;Vol.46:249-253;Ozcanet al.,Int Ophthalmol.,2004;Vol.25:19-22]。还报道了TGF-β2亚型增加细胞外基质(ECM)的产生。[Kottler et al.,Exp EyeRes.,2005;Vol.80:121-134]。在原发性开角型青光眼中,在眼睛的小梁网(TM)区域内细胞外基质的不相称增生被认为给予了房水外流更大的阻力,导致眼内压升高。[Rohen et al.,Graefe’sArch KlinExp Ophthalmol.,1972;Vol.183:251-266;Lee et al.,TransOphthalmol Soc UK.,1974;Vol.94:430-449]。因此,在房水中升高的TGF β2水平和升高的眼内压之间可能存在着直接的联系。
发明概要
本发明部分地涉及治疗在人类患者或其他哺乳动物中青光眼的方法。本发明还涉及降低或控制在人类患者或其他哺乳动物中正常或升高的眼内压的方法。
本发明的实施方案通过调节ALK5受体的活性来控制眼内压和治疗青光眼。在体外试验中,TGF-β2作用在ALK5(1型TGF-β受体)上导致在小梁网(TM)内细胞外基质(ECM)蛋白质的产生增加。因此推定在体内,TGF-β2诱导的在小梁网内细胞外基质产生的增加最终导致眼内压增加。因此,对TGF-β2介导反应作用的下调给出了降低和/或控制眼内压和治疗青光眼的潜在的方法。例如,ALK5活性的抑制预计将导致TGF-β2介导的ECM累积的减少。因此,如果在这样一个***中引入一种抑制或选择性调节ALK5受体的化合物,TGF-β2对眼内压的不良作用将被减少或改善。
更进一步,TGF-β亚型1、2和3是属于经过跨膜丝氨酸/苏氨酸激酶受体传递信号的细胞因子家族;这个超家族的其他成员包括活化素、抑制素、骨形态发生蛋白质、生长和分化因子和米勒抑制物质。TGF-beta亚型的受体被分组为两种类型:I型或活化素样激酶(ALK5或ALK1)受体和I I型受体。TGF-β信号传递是在存在TGF-β情况下经由I I型受体磷酸化I型受体,例如,ALK5完成的。活化的ALK5,依次磷酸化胞质蛋白质Smad2和Smad3。然后磷酸化的Smad2和Smad3蛋白质与另一种Smad蛋白质,Smad4,形成了一种复合物。产物Smad蛋白质复合物随后移位进入细胞核并驱动基因转录。
在这里使用时,术语“选择性ALK5调节剂”或“选择性调节剂”指一种试剂,除了抑制Smad蛋白质(例如,Smad6和Smad7)之外,其抑制ALK5自身的激活/磷酸化或抑制ALK5激活/磷酸化它的靶Smad蛋白质的能力。所述的药物优先抑制ALK5受体,超过其他ALK类型受体,例如ALK3,其调节经由骨形态形成蛋白质的信号传递。与II型受体或其他信号传递激酶例如p38MAPK相比,所述的药物也优先抑制ALK5受体。例如,已经报道与TGF-βII型受体和p 38MAPK的磷酸化相比(IC50分别为10μM和9.5μM),GW-6604有效的抑制ALK5的磷酸化(I C50-0.14μM)。Brit J Pharmacol.,2005;Vol.145:166-177。
本发明的某些实施方案包括组合物或方法,所述组合物或方法包括或使用能选择性调节ALK5受体活性从而调节眼内的眼内压的化合物。细胞因子,例如TGF-β2,或其他化合物与ALK5受体的交互作用可以导致在小梁网内细胞外基质蛋白质产生的改变,从而调节眼内压。因此,通过调节ALK5受体的活性,根据本发明某些实施方案的目标化合物有益于降低和/或控制在人类和其他恒温动物内与正常张力青光眼、眼高压和青光眼有关的眼内压,所述青光眼包括原发性开角型青光眼。当在这种应用中使用时,化合物可以被配制在适合用于对眼睛局部给药的药物组合物中。
在本发明的另一个实施方案中,一种体外的方法来筛选对于ALK5受体活性的选择性调节剂。所述筛选能帮助选择新的用于治疗青光眼和控制眼内压的化合物。所述方法包括在适当的生长培养基中培养小梁网细胞。所述培养的细胞被分成重复和/或实验和/或对照组,向其中添加对照溶液或包含ALK5活性选择性调节剂的实验溶液。随后测量在每种细胞培养组中的细胞外基质关联蛋白,例如纤连蛋白、纤溶酶原激活物抑制剂I(PAI-1)、胶原、原纤蛋白、玻璃体结合蛋白、层粘连蛋白、血小板反应蛋白I、蛋白聚糖或整联蛋白的水平。然后可以在组之间比较细胞外基质蛋白水平,以确定包含对ALK5活性的选择性调节剂的实验溶液的作用。
上述概要大致的描述了本发明的某些实施方案的特征和技术效果。在随后的发明内容部分将描述另外的特征和技术效果。当结合所有的附图考虑时,将从发明内容更好的理解被认为是本发明特有的新颖的特征。然而,这里给出的图是用来帮助理解发明或帮助发明理解的扩展,而不是用来定义发明的范围。
附图说明
通过参考下列描述,连同附图可以获得对本发明和其优点更完整的理解,所述附图中同样的引用编号代表同样的特征,和其中:
图1显示注入TGF-β2对灌流人眼前房部分模型的眼内压的作用与对照组相比的结果图;
图2显示ALK5抑制剂对在TGF-β2处理的灌流人眼前房部分模型中纤连蛋白水平的作用与对照组相比的结果图;
图3给出图,显示添加不同浓度的ALK5抑制剂的体外小梁网细胞培养物中纤连蛋白和PAI-1的测量水平;和
图4给出图,显示在体外小梁网细胞培养物中前胶原I型C-肽(PIP)的测量水平。
发明内容
本发明的某些实施方案包括化合物、组合物或方法,所述化合物、组合物或方法包括或使用能选择性调节ALK5受体活性从而调节眼内的眼内压的化合物。已经发现具有ALK5调节活性的具体典型化合物列于下面。在优选实施方案中,用于实施本发明方法的化合物包括如下所示的化合物1和2。在另一个实施方案中,可以使用下列化合物的一个或多个:
上面所示的某些化合物可以用厂商的命名来引用。这包括化合物1(SB-431542),化合物2(LY-364947),化合物3(LY-550410),化合物4(LY-580276),化合物5(SB-504124),化合物12(GW-6604),化合物13(A-83-01),化合物14(SB-525334)和化合物15(SC-68376)。除上述化合物之外,或在其他实施方案中,可以使用列于下面组I和I I中下列化合物的一种或多种:
组I:
4-(3-(6-甲基吡啶-2-基)-1H-吡唑-4-基)-7-乙氧基喹啉;4-(3-吡啶-2-基-1H-吡唑-4-基)-7-乙氧基喹啉;7-氟-4-[3-(6-甲基-吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-溴代吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-[正-丁基氨基]吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;6-氯-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;6-三氟甲基-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;7-甲基-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;6-甲氧基-4-[3-1H-吡唑-4-基]-喹啉;6-三氟甲氧基-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(3-氯苯基)-1H-吡唑-4-基]-喹啉;6-丁氧基-4-(3-吡啶-2-基-1H-吡唑-4-基)-喹啉;6-仲-丁基-4-(3-吡啶-2-基-1H-吡唑-4-基)-喹啉;5-甲基-3-(6-甲基吡啶-2-基)-4-(-4-氟苯基)-1H-吡唑;4-(4-甲氧苯基)-5-甲基-3-(6-甲基吡啶-2-基)-1H-吡唑;4-[5-甲基-3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-丙基吡啶-2-基)-1H-吡唑-4-基]-喹啉;3-环丙基-5-吡啶-2-基-4-喹啉-4-基-吡唑;3-(3-三氟甲基苯基)-4-喹啉-4-基-吡唑;1-苯甲基-3-(2-吡啶基)-4-(4-喹啉基)吡唑;1-(4-苯丁基)-3-(2-吡啶基)-4-(4-喹啉基)吡唑;2-(3-(2-吡啶基)-4-(4-喹啉基)吡唑基)乙-1-醇;2-(3-(2-吡啶基)-4-(4-喹啉基)吡唑基)乙基甲磺酸酯;4-[2-(3-(2-吡啶基)-3-(4-喹啉基)-吡唑基)乙基]吗啉;苯基[2-(3-(2-吡啶基)-4-(4-喹啉基)-吡唑基)乙基]胺;4-(4-吡啶-2-基-1H-吡唑-3-基)-喹啉;和4-(3-吡啶-2-基-1H-吡唑-4-基)-喹啉。
组II:
5-[5-(6-甲基吡啶-2-基)-1H-[1,2,3]***-4-基]-苯并[1,2,5]噻二唑;5-[2-乙基-5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基]-苯并[1,2,5]噻二唑;6-[5-(6-甲基吡啶-2-基)-1H-[1,2,3]***-4-基]-[1,2,4]***并[1,5-a]吡啶;2-[5-(2,3-二氢苯并呋喃-5-基)-3H-[1,2,3]***-4-基]-6-甲基吡啶;2-[5-(2,3-二氢苯并[1,4]二噁英-6-基)-2H-[1,2,3]***-4-基]-6-甲基吡啶;1-甲基-6-[5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基]-1H-苯并咪唑;6-(2-乙基-5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基)-[1,2,4]***并[1,5-a]吡啶;6-(2-甲基-5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基)-[1,2,4]***并[1,5-a]吡啶;2-[5-(4-甲氧苯基)-2H-[1,2,3]***-4-基]-6-甲基吡啶;2-[5-(3-氟-4-甲氧苯基)-2H-[1,2,3]***-4-基]-6-甲基吡啶;和2-[5-(3-氯-4-甲氧苯基)-2H-[1,2,3]***-4-基]-6-甲基吡啶。
从上述化合物的集合中,下列可以通过商业来源获得:1、由Sigma,P.O.Box 14508,St.Louis,MO,63178-9916市售;2、由Matrix Scientific,P.O.Box 25067,Columbia,SC,29224-5067市售;和15、由G.Scientific,Inc.,6450Lusk Blvd.Suite E102,San Diego,CA,92121市售。
其他化合物可以按如下来源参考文献所述来合成[格式:化合物编号,合成参考文献]:
3和4,Sawyer et al.,Bioorganic and Medicinal ChemistryLetters,2004;Vol.14:3581-3584;
5和14,WO 2001/062756A1;
6,WO 2004/026871;
7,Gellibert et al.,Journal of Medicinal Chemistry,2004;Vol.47:4494-4506;
8,WO 2004/021989;
9,WO 2004/026307;
10,WO 2000/012497;
11,WO 2004/147574;
16,Kim et al.,Bioorganic and Medicinal Chemistry Letters,2004;Vo l.12:2013-2020;
12,WO 2002/066462;
13,Tojo et al.,Cancer Science,2005;Vol.96:791-800;
17-21,WO 2004/016606;
22,美国专利申请公开号2004/116474;
23和24,Sawyer et al.,Journal of Medicinal Chemistry,2003;Vol.46:3953-3956;
组I化合物,WO 2004/026302;和
组II化合物,美国专利申请公开号US 2004/152738。
上述给出的化合物决不是打算限制本发明的范围。本发明的范围包括能被确定为具有选择性控制、抑制或调节活化素受体样激酶5(ALK5;或I型TGF-β受体)活性的能力的任何药物。
图1是一幅显示注入TGF-β2对灌流人眼前房部分模型作用的图。在所述模型中使用的所有捐献者眼睛都按照赫尔辛基宣言对于包括人体组织研究的规定来使用,并是在死后24小时内使用。已知没有捐献者具有青光眼或其他眼疾病史。
按照现有文献的记载来进行人眼灌流器官培养。[Tschumper etal.,CurrEye Res.,1990;Vol.9:363-369;Clark et al.,InvestOphthalmol Vis Sci.,1995;Vol.36:478-489;Pang et al.,JGlaucoma,2000;Vol.9:468-479;Pang et al.,Invest OphthalmolVis Sci.,2003;Vol.44:3502-3510]。简要地说,眼前房部分被解剖并安装到定制的树脂玻璃培养室中,然后用无血清Dulbecco’s改良Eagle’s培养基灌流。每5秒钟监测眼内压并平均到每个小时。让灌流组织在37℃和5%CO2下平衡直到出现稳定的眼内压基线,一般要2-4天;弃去眼内压不稳定的组织。随后,稳定的组织被进一步灌流包含所示试验化合物的培养基,并记录眼内压的变化。每天采集洗出样品用于纤连蛋白和PAI-1含量的酶联免疫吸附(ELISA)分析。在每个研究的最后,组织被固定并通过光学和电子显微镜评价生存力/形态学。来源于不合格组织的数据被从结果中去除。“不合格”组织的标准包括发现例如在小梁网区域过量的碎片、小梁网横梁的溶蚀、小梁网和/或巩膜静脉窦细胞的损失和巩膜静脉窦的破裂或塌陷。
在图1中显示的结果表明用5ng/mL的TGF-β2输注的灌流人眼前房部分模型在24小时内与对照组相比产生了眼内压升高。在72小时后,接受TGF-β2灌流的模型的眼内压几乎是对照组的一倍。
如上推定,具有选择性ALK5调节活性的化合物的引入降低或改善了TGF-β2诱导的细胞外基质产生的不良作用。在图2中,给出的试验结果显示与仅用TGF -β2灌流的对照模型相比,来自用TGF-β2和如下所示的化合物1处理的人眼前房部分的灌流液中纤连蛋白的水平降低了。化合物1完全地对抗了TGF-β2介导的在灌注液中纤连蛋白含量的增加。
图3显示了使用培养的人小梁网细胞的研究的汇总结果图。以前已经描述了GTM-3转化细胞系的繁殖和表征(Pang et al.,Curr EyeRes.,1994;Vol.13:51-63)。简要的说,保持生长培养基由补充了10%胎牛血清(Hyclone,Logan,UT)的具有Glutamax I(Gibco/BRL,Grand Is land,NY)的Dulbecco’s改良Eagle’s培养基和50μg/mL庆大霉素(Gibco/BRL)组成。为了分析,培养物被胰蛋白酶化和接种到24孔盘(Corning Costar,Acton,MA)中,并让其生长到单层达到大约90%融合。然后,培养基被替换为0.25mL包含适当试验化合物的无血清和无抗生素培养基。细胞在5%CO2和37℃下被培养24h。随后,培养物上清液的等分试样通过ELISA分析纤连蛋白和/或PAI-1含量。
在图3中显示的研究结果揭示了ALK5调节化合物1和2对来自人小梁网细胞培养物的上清液中由TGF-β2介导的纤连蛋白和PAI-1的含量增加的剂量依赖抑制作用。
图4显示了在人小梁网细胞培养物中前胶原I型C-肽(PIP)的测量水平的汇总图。对于所示试验,培养的转化GTM-3细胞(Pang etal.,Curr Eye Res.,1994;Vol.13:51-63)生长在由补充了10%胎牛血清(Hyclone,Logan,UT)的具有Glutamax I(Gibco/Invitrogen,Grand Is land,NY)的Dulbecco’s改良Eagle’s培养基和50μg/mL庆大霉素(Gibco/Invitrogen)组成的生长培养基中。为了分析,培养物被酶化分离(TrypLE Express;Gibco/Invitrogen),然后接种到24孔盘(Corning Costar,Acton,MA)中,并让其生长到单层达到大约90%-95%融合。然后,培养基被替换为0.25mL包含适当试验化合物的无血清和无抗生素培养基。细胞在5%CO2和37℃下培养24h。然后培养物上清液的等分试样被使用ELISA试剂盒(TaKaRa Bio,Shiga,Japan)分析前胶原I型C-肽。
胶原由前胶原合成,大部分前胶原包含被称为“前肽”的附加肽序列。前肽位于分子的N和C末端两处。这些前肽用来促进在内质网内从前胶原形成成熟的胶原三链螺旋结构。随后在分泌时前肽部分被从三链螺旋胶原分子裂解-因此游离前肽,例如PIP的浓度能被用于关联到细胞合成的胶原数量的变化。与载体组相比,两个重复研究的结果显示在TGF-β2处理的培养物中PIP水平被显著的升高。然而,当使用TGF-β2和ALK5调节化合物1两者处理培养物时,所述TGF-β2依赖性PIP升高被消除了。因此,图4中给出的研究结果表明TGF-β2介导的PIP水平增加被ALK5调节化合物1抑制。假定PIP水平与胶原生产直接相关,ALK5调节剂例如化合物1显示出减少胶原生产,和因此将抑制在小梁网内的整体细胞外基质蛋白质生产。
下述表1概括了测量TGF-β2在培养的小梁网细胞的各种株中对细胞外基质相关蛋白质水平(纤连蛋白,PAI-1)作用的研究结果。在培养物中TGF-β2的存在浓度为5ng/mL,并在24小时后测量蛋白质水平(平均数±标准误(mean±s.e.m.)。表的结果表明在各种人小梁网细胞培养物中TGF-β2增加纤连蛋白和PAI-1的产生。
表1:TGF-β2对人小梁网细胞分泌纤连蛋白和PAI-1的作用
从上面概括的结果看,适当的结论是用包含和使用具有调节ALK5受体活性作用的化合物的组合物和方法可以有效的控制眼内压和治疗青光眼。
根据本发明某些实施方案使用的选择性调节化合物可以被加入各种类型的用于给药的眼用制剂。所述化合物可以直接向眼睛给药(例如:局部眼用滴剂或软膏;在盲管中或植入邻近巩膜或在眼睛内部的缓释装置;眼周的、结膜的、眼球囊下、眼房内、玻璃体内或小管内的注射剂)。在某些实施方案中,化合物可以使用本领域技术人员已知的技术来全身给药(例如:口服;静脉的、皮下的或肌肉注射;肠道外;皮肤或鼻给药)。更进一步的期望本发明的试剂可以配制在眼内***或植入装置内。
在优选实施方案中,根据本发明的选择性调节化合物被加入到对眼睛给药的局部眼用制剂中。所述化合物可以与眼用可接受的防腐剂、表面活性剂、粘性增强剂、渗透增强剂、缓冲液、氯化钠和/或水结合来形成含水的、无菌眼用混悬液或溶液。可以通过把化合物溶解于生理可接受的等渗含水缓冲液中制备眼用溶液制剂。更进一步,所述眼用溶液可以包括眼用可接受的表面活性剂以帮助溶解化合物。所述眼用溶液还可以包含试剂来增加粘性,例如,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,用以改善制剂在结膜囊内的保留。还可以使用胶凝剂,包括但不限于,吉兰糖和黄原胶。
为了制备无菌眼用软膏制剂,选择性调节化合物在适当的载体中,例如,矿物油、液体羊毛脂或白凡士林与防腐剂结合。无菌眼用凝胶制剂可以通过悬浮所述化合物在亲水基质中制备,所述亲水基质根据已经公开的用于类似眼用的制剂的配方的综合来制备,例如,ca rbopo1-974等等;还可以加入防腐剂和张力试剂。
在某些实施方案中,选择性调节化合物优选被配制为局部眼用混悬液或溶液,具有约4到8的pH。通常所述化合物以重量/体积比百分之0.01到5(“w/v%”)的数量包含在这些制剂中,但优选在0.25到2w/v%数量内。根据熟练临床医师的判断,典型的给药方案将包括每天1到4次给予这些制剂的1到2滴到眼睛的表面。
所述选择性调节化合物还可以与其他用于治疗青光眼的药物结合使用,例如,但不限于,β-阻断剂,***素类似物,碳酸酐酶抑制剂,α2激动剂,缩瞳药,和神经保护剂。
本发明的某些实施方案包括体外筛选用于治疗青光眼和控制眼内压的ALK5受体活性选择性调节剂的方法。通常,这些实施方案包括在合适的培养基中培养大量的小梁网细胞。在某些实施方案中,小梁网细胞可以根据在图3中描述的小梁网培养步骤来培养。ALK5活性的选择性调节剂被添加到培养细胞的第一群。在这些实施方案中,还制备了不具有选择性调节剂的对照群。然后,对每个存在和不存在TGF-β2的细胞培养群测定细胞外基质蛋白质,例如纤连蛋白或PAI-1的水平。在本发明的实施方案中能测量任意细胞外基质蛋白质。然后比较第一群和对照群的测量水平。这种比较可以被用于筛选对于ALK5受体活性的选择性调节剂,并用于确定是否所述选择性调节剂将被用于治疗青光眼和控制眼内压。
如下所示的是根据本发明实施方案的药物组合物的几个实施例。下列实施例是用来说明本发明的实用性,而不应被看作暗示对权利要求的任何限制。
实施例1
成分 | 浓度(w/v%) |
化合物1 | 0.01-2% |
羟丙基甲基纤维素 | 0.5% |
磷酸二氢钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酸酯80 | 0.05% |
洁尔灭 | 0.01% |
氢氧化钠/盐酸 | 用于调整pH为7.3-7.4 |
净化水 | 适量至100% |
实施例2
成分 | 浓度(w/v%} |
化合物2 | 0.01-2% |
甲基纤维素 | 4.0% |
磷酸二氢钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酸酯80 | 0.05% |
洁尔灭 | 0.01% |
氢氧化钠/盐酸 | 用于调整pH为7.3-7.4 |
净化水 | 适量至100% |
实施例3
成分 | 浓度(w/v%} |
化合物13 | 0.01-2% |
瓜耳豆胶 | 0.4-6.0% |
磷酸二氢钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酸酯80 | 0.05% |
洁尔灭 | 0.01% |
氢氧化钠/盐酸 | 用于调整pH为7.3-7.4 |
净化水 | 适量至100% |
实施例4
成分 | 浓度(w/v%) |
化合物12 | 0.012% |
白凡士林和矿物油和羊毛脂 | 软膏稠度 |
磷酸二氢钠(无水) | 0.2% |
氯化钠 | 0.5% |
EDTA二钠(依地酸二钠) | 0.01% |
聚山梨酸酯80 | 0.05% |
洁尔灭 | 0.01% |
氢氧化钠/盐酸 | 用于调整pH为7.3-7.4 |
已经详细描述了本发明及其实施例。然而,本发明的范围将不意图被限于具体描述的任何工艺、制造、物质的组合、化合物、方式、方法和/或步骤。在不偏离本发明的精神和/或本质特征的条件下可以对公开的材料作出各种改良、替换和改变。因此,本领域普通技术人员将易于理解,可以根据本发明的所述相关实施方案使用新的改良、替换和/或改变,所述改良、替换和/或改变执行与本文所述的实施方案有基本相同的功能或实现基本相同的结果。因而,权利要求被用来涵盖它们范围内的对本文公开的工艺、制造、物质的组合、化合物、方式、方法和/或步骤的改良、替换和改变。
Claims (15)
1、一种用于治疗青光眼和控制眼内压的眼用药物组合物,包含:有效量的ALK5受体活性的选择性调节剂。
2、如权利要求1所述的组合物,其中所述选择性调节剂选自:
4-(3-(6-甲基吡啶-2-基)-1H-吡唑-4-基)-7-乙氧基喹啉;4-(3-吡啶-2-基-1H-吡唑-4-基)-7-乙氧基喹啉;7-氟-4-[3-(6-甲基-吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-溴代吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-[正-丁基氨基]吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;6-氯-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;6-三氟甲基-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;7-甲基-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;6-甲氧基-4-[3-1H-吡唑-4-基]-喹啉;6-三氟甲氧基-4-[3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(3-氯苯基)-1H-吡唑-4-基]-喹啉;6-丁氧基-4-(3-吡啶-2-基-1H-吡唑-4-基)-喹啉;6-仲-丁基-4-(3-吡啶-2-基-1H-吡唑-4-基)-喹啉;5-甲基-3-(6-甲基吡啶-2-基)-4-(-4-氟苯基)-1H-吡唑;4-(4-甲氧苯基)-5-甲基-3-(6-甲基吡啶-2-基)-1H-吡唑;4-[5-甲基-3-(6-甲基吡啶-2-基)-1H-吡唑-4-基]-喹啉;4-[3-(6-丙基吡啶-2-基)-1H-吡唑-4-基]-喹啉;3-环丙基-5-吡啶-2-基-4-喹啉-4-基-吡唑;3-(3-三氟甲基苯基)-4-喹啉-4-基-吡唑;1-苯甲基-3-(2-吡啶基)-4-(4-喹啉基)吡唑;1-(4-苯丁基)-3-(2-吡啶基)-4-(4-喹啉基)吡唑;2-(3-(2-吡啶基)-4-(4-喹啉基)吡唑基)乙-1-醇;2-(3-(2-吡啶基)-4-(4-喹啉基)吡唑基)乙基甲磺酸酯;4-[2-(3-(2-吡啶基)-3-(4-喹啉基)-吡唑基)乙基]吗啉;苯基[2-(3-(2-吡啶基)-4-(4-喹啉基)-吡唑基)乙基]胺;4-(4-吡啶-2-基-1H-吡唑-3-基)-喹啉;和4-(3-吡啶-2-基-1H-吡唑-4-基)-喹啉;5-[5-(6-甲基吡啶-2-基)-1H-[1,2,3]***-4-基]-苯并[1,2,5]噻二唑;5-[2-乙基-5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基]-苯并[1,2,5]噻二唑;6-[5-(6-甲基吡啶-2-基)-1H-[1,2,3]***-4-基]-[1,2,4]***并[1,5-a]吡啶;2-[5-(2,3-二氢苯并呋喃-5-基)-3H-[1,2,3]***-4-基]-6-甲基吡啶;2-[5-(2,3-二氢苯并[1,4]二噁英-6-基)-2H-[1,2,3]***-4-基]-6-甲基吡啶;1-甲基-6-[5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基]-1H-苯并咪唑;6-(2-乙基-5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基)-[1,2,4]***并[1,5-a]吡啶;6-(2-甲基-5-(6-甲基吡啶-2-基)-2H-[1,2,3]***-4-基)-[1,2,4]***并[1,5-a]吡啶;2-[5-(4-甲氧苯基)-2H-[1,2,3]***-4-基]-6-甲基吡啶;2-[5-(3-氟-4-甲氧苯基)-2H-[1,2,3]***-4-基]-6-甲基吡啶;和2-[5-(3-氯-4-甲氧苯基)-2H-[1,2,3]***-4-基]-6-甲基吡啶。
3、如权利要求1所述的组合物,包含所述选择性调节剂的药学上可接受的盐。
4、如权利要求1所述的组合物,进一步包含化合物,所述化合物选自:
眼用可接受的防腐剂、表面活性剂、粘性增强剂、渗透增强剂、胶凝剂、疏水基质、载体、缓冲液、氯化钠和水。
5、如权利要求1所述的组合物,进一步包含青光眼治疗药物。
6、如权利要求5所述的组合物,其中所述青光眼治疗药物选自:
β-阻断剂,***素类似物,碳酸酐酶抑制剂,α2激动剂,缩瞳药和神经保护剂。
7、如权利要求1所述的组合物,其中所述组合物包含从约0.01%重量/体积到约5%重量/体积的所述化合物。
8、如权利要求1所述的组合物,其中所述组合物包含从约0.25%重量/体积到约2%重量/体积的所述化合物。
9、如权利要求1所述的组合物,其中所述组合物进一步包含防腐剂、张力试剂、抗氧化剂、稳定剂、润湿剂、澄清剂或粘性增加试剂。
10、体外筛选用于治疗青光眼和控制眼内压的ALK5受体活性的选择性调节剂的方法,包括:
在合适的培养基中培养大量小梁网(TM)细胞;
向所述小梁网细胞的第一群中添加所述选择性调节剂;和
比较在所述第一群和对照群中的细胞外基质相关蛋白质的测量水平。
11、如权利要求10所述的方法,其中所述细胞外基质相关蛋白质选自:
纤连蛋白、纤溶酶原激活物抑制剂I(PAI-1)、胶原、原纤蛋白、玻璃体结合蛋白、层粘连蛋白、血小板反应蛋白I、蛋白聚糖和整联蛋白。
12、治疗青光眼和控制眼内压的方法,包括:
向患者受影响的眼睛应用治疗有效量的包含ALK5受体活性选择性调节剂的药物组合物。
13、如权利要求12所述的方法,其中所述应用包括:
应用权利要求2所述的组合物。
14、如权利要求13所述的方法,其中所述的应用包括使用选自如下的技术:
眼周注射、结膜注射、眼球囊下注射、眼房内注射、玻璃体内注射、小管内注射、在盲管中的植入给药装置、邻近巩膜的植入给药装置、在眼内的植入给药装置、口服给药、静脉内给药、皮下给药、肌肉给药、肠胃外给药、皮肤给药和鼻给药。
15、如权利要求12所述的方法,其中所述药物组合物包含防腐剂、张力试剂、抗氧化剂、稳定剂、润湿剂、澄清剂或粘性增加试剂。
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BR0314302A (pt) * | 2002-09-18 | 2005-07-05 | Pfizer Producs Inc | Compostos de pirazol como inibidores do fator de crescimento trnasformante (tgf) |
CA2498047C (en) * | 2002-09-18 | 2009-05-19 | Pfizer Products Inc. | Novel imidazole compounds as transforming growth factor (tgf) inhibitors |
WO2004065392A1 (en) * | 2003-01-24 | 2004-08-05 | Smithkline Beecham Corporation | Condensed pyridines and pyrimidines and their use as alk-5 receptor ligands |
JP2006516603A (ja) * | 2003-01-27 | 2006-07-06 | ファイザー・プロダクツ・インク | イソチアゾール誘導体 |
PA8595001A1 (es) * | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
CA2517720A1 (en) * | 2003-03-11 | 2004-09-23 | Pfizer Products Inc. | Pyrazine compounds as transforming growth factor (tgf) inhibitors |
US20050136043A1 (en) * | 2003-08-07 | 2005-06-23 | Ludwig Institute For Cancer Research | TGFbeta signaling inhibitors |
JP2005060360A (ja) * | 2003-08-19 | 2005-03-10 | Jun Yamada | 眼科用医薬品 |
DK1740164T3 (da) * | 2004-04-26 | 2008-11-10 | Alcon Inc | Statine til behandling af okulær hypertension og glaukom |
-
2006
- 2006-12-15 ZA ZA200804496A patent/ZA200804496B/xx unknown
- 2006-12-15 AU AU2006325706A patent/AU2006325706B2/en not_active Ceased
- 2006-12-15 JP JP2008545986A patent/JP2009519977A/ja not_active Ceased
- 2006-12-15 KR KR1020087013390A patent/KR20080082618A/ko not_active Application Discontinuation
- 2006-12-15 CA CA002629432A patent/CA2629432A1/en not_active Abandoned
- 2006-12-15 BR BRPI0619966-6A patent/BRPI0619966A2/pt not_active IP Right Cessation
- 2006-12-15 WO PCT/US2006/062151 patent/WO2007070866A2/en active Application Filing
- 2006-12-15 CN CNA2006800473526A patent/CN101330914A/zh active Pending
- 2006-12-15 US US11/611,312 patent/US20070142376A1/en not_active Abandoned
- 2006-12-16 EP EP06840280A patent/EP1959949A2/en not_active Withdrawn
-
2011
- 2011-03-08 US US13/042,848 patent/US20110160210A1/en not_active Abandoned
-
2012
- 2012-01-11 US US13/348,376 patent/US20120115870A1/en not_active Abandoned
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102695511A (zh) * | 2009-04-17 | 2012-09-26 | 舒玛健康***有限责任公司 | 抑制眼部瘢痕形成的转化生长因子-β受体抑制剂的用途 |
CN110066277A (zh) * | 2018-01-24 | 2019-07-30 | 上海璎黎药业有限公司 | 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 |
WO2019144765A1 (zh) * | 2018-01-24 | 2019-08-01 | 上海璎黎药业有限公司 | 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 |
CN110066277B (zh) * | 2018-01-24 | 2021-07-23 | 上海璎黎药业有限公司 | 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 |
US11447490B2 (en) | 2018-01-24 | 2022-09-20 | Shanghai Yingli Pharmaceutical Co., Ltd | Aromatic heterocyclic substituted olefin compound, preparation method for same, pharmaceutical composition of same, and applications thereof |
Also Published As
Publication number | Publication date |
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EP1959949A2 (en) | 2008-08-27 |
WO2007070866A3 (en) | 2008-01-03 |
BRPI0619966A2 (pt) | 2011-10-25 |
AU2006325706A1 (en) | 2007-06-21 |
JP2009519977A (ja) | 2009-05-21 |
KR20080082618A (ko) | 2008-09-11 |
ZA200804496B (en) | 2009-09-30 |
US20110160210A1 (en) | 2011-06-30 |
US20070142376A1 (en) | 2007-06-21 |
WO2007070866A2 (en) | 2007-06-21 |
CA2629432A1 (en) | 2007-06-21 |
US20120115870A1 (en) | 2012-05-10 |
AU2006325706B2 (en) | 2012-03-29 |
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