CN110869346B - 纤维蛋白溶酶原活化物抑制因子-1(pai-1)抑制剂和使用方法 - Google Patents
纤维蛋白溶酶原活化物抑制因子-1(pai-1)抑制剂和使用方法 Download PDFInfo
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- CN110869346B CN110869346B CN201880045871.1A CN201880045871A CN110869346B CN 110869346 B CN110869346 B CN 110869346B CN 201880045871 A CN201880045871 A CN 201880045871A CN 110869346 B CN110869346 B CN 110869346B
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Abstract
本文提供纤维蛋白溶酶原活化物‑1(PAI‑1)抑制剂化合物和其在治疗与PAI‑1升高相关的任何疾病或病症中的用途。本公开包括(但不限于)使用这类化合物来预防或减少血栓形成和纤维化、促进血栓溶解和调节脂质代谢以及治疗与PAI‑1、胆固醇或脂质水平升高相关的疾病或病症。
Description
政府支持声明
本发明是在政府支持下在由美国国家卫生研究院(National Institutes ofHealth)授予的HL089407下进行。政府对本发明享有一定权利。
技术领域
本文提供用于调节纤维蛋白溶酶原活化物抑制因子-1(PAI-1)活性的化合物和方法。更确切地说,本公开涉及PAI-1抑制剂和这类抑制剂在调节PAI-1活性中的用途。还提供了这些抑制剂用于治疗与PAI-1活性相关的许多疾病或病症中的用途。这类疾病或病症包括(但不限于)脂质代谢异常、肥胖症、糖尿病、多囊性卵巢综合征、由雌激素缺乏引起的骨质损失、纤维化和纤维化疾病、炎症、细胞迁移和迁移驱动的细胞增殖、血管生成和血栓形成。还预期这类抑制剂适用于调节内源性纤维蛋白溶解,并且与药理学血栓溶解结合。
背景技术
纤维蛋白溶酶原活化物抑制因子-1(PAI-1)是一种50kDa单链糖蛋白,其是尿激酶型纤维蛋白溶酶原活化物(uPA)和组织型PA(tPA)两者的主要抑制因子。PAI-1抑制tPA和uPA,其二级速率常数是约107M-1s-1(比其它PAI的PA抑制速率快10到1000倍的值)。此外,在谨慎收集的正常人类血浆中,检测到约70%的总tPA与PAI-1复合,表明PAI-1对tPA的抑制是正常持续的过程。PAI-1还可直接抑制纤维蛋白溶酶。因此,PAI-1是活体内纤维蛋白溶酶生成的首要调节因子,并且因此其似乎在纤维化和血栓性疾病两者中起重要作用。PAI-1具有三个潜在的N-连接糖基化位点并且含有介于15%与20%之间的碳水化合物。
PAI-1属于丝氨酸蛋白酶抑制因子超家族(Serine Protease Inhibitor superfamily,SERPIN),其是一种包括许多在血液中发现的蛋白酶抑制因子以及具有不相关或未知功能的其它蛋白的基因家族。丝氨酸蛋白酶抑因子(serpin)在蛋白酶失活过程中被消耗,并且因此充当“自杀性抑制因子”。丝氨酸蛋白酶抑因子与其目标蛋白酶之间的缔合发生在位于丝氨酸蛋白酶抑因子的表面环(称为反应性中心环(RCL))上的氨基酸残基(称为“诱饵”残基)处。“诱饵”残基也被称为P1残基,并且被认为模拟酶的正常底物。当P1残基与目标蛋白酶S1位点缔合时,发生RCL的裂解。这与丝氨酸蛋白酶抑因子中的大型构象变化耦合,所述构象变化涉及将RCL快速插入到丝氨酸蛋白酶抑因子的主要结构特征β片层A中。这使蛋白酶与丝氨酸蛋白酶抑因子表面紧密对接和酶结构(包括其活性位点)的失真。RCL插入还大大增加了丝氨酸蛋白酶抑因子的结构稳定性,使得复合物具有刚性,并且因此在与丝氨酸蛋白酶抑因子的共价酰基酶复合物中捕获蛋白酶。
原生PAI-1以至少两种不同构象存在,一种是由细胞产生和分泌的活性形式,另一种是随着时间在细胞培养基中累积的非活性或潜伏形式。在血液和组织中,大多数PAI-1呈活性形式;然而,在血小板中发现了活性形式和潜伏形式两者的PAI-1。在活性PAI-1中,RCL暴露在分子表面上,但在与蛋白酶反应时,裂解的RCL整合到β片层A的中心。在潜伏形式中,RCL是完整的,但RCL的整个氨基末端侧不是暴露的,而是作为中心链插入到β片层A中。这解释了潜伏的PAI-1稳定性增加以及其抑制活性缺乏。
活性PAI-1在37℃下自发地转化成潜伏形式,半衰期为一小时到两小时,而潜伏的PAI-1可通过用变性剂处理而转换回活性形式。带负电荷的磷脂也可以将潜伏的PAI-1转化成活性形式,表明细胞表面可调节PAI-1活性。输注到兔中的潜伏的PAI-1明显转换成活性形式的观察结果与此假说一致。活性结构与潜伏结构之间的自发可逆的互转化对于PAI-1是独特的,并将其与其它丝氨酸蛋白酶抑因子区分开来;然而,潜伏构象的生物学意义仍然未知。
还鉴别了其它非抑制形式的PAI-1。第一种形式是由对活性PAI-1内的一个或多个关键蛋氨酸残基的氧化产生。这种形式与潜伏的PAI-1不同之处在于,它可由特异性还原经过氧化的蛋氨酸残基的酶来部分再活化。PAI-1的氧化失活可能是调节PAI-1的额外机制,并且由嗜中性白细胞或其它细胞局部产生的氧基可能使得PAI-1失活,并且因此促进在感染部位或组织重构区域生成纤维蛋白溶酶。PAI-1还以两种不同的裂解形式存在。如上所述,与蛋白酶复合的PAI-1裂解成其RCL。还可发现其中RCL裂解的未复合的PAI-1,这可能是由于PAI-1-PA复合物的解离或非目标蛋白酶在除P1之外的位点对RCL的裂解所致。这些形式的PAI-1都无法抑制蛋白酶活性;然而,这些形式的PAI-1可能与其它配体相互作用。
PAI-1与非蛋白酶配体的相互作用在PAI-1功能方面起到至关重要的作用。PAI-1以高亲和力结合于肝素、细胞粘附蛋白玻连蛋白和内吞性低密度脂蛋白受体(LDL-R)家族成员(如脂蛋白受体相关蛋白(LRP))和极低密度脂蛋白受体(VLDL-R)。这些非蛋白酶相互作用对于PAI-1定位和功能都是重要的,并且很大程度上通过与RCL插入相关的结构变化以构象方式受到控制。在血液中,大多数活性PAI-1以与糖蛋白玻连蛋白复合的形式循环。玻连蛋白的PAI-1结合位点已定位于PAI-1结构中的β片层A边缘上的区域。LDL-R家族成员的结合位点没有得到充分表征,但已被鉴别,其位于与玻连蛋白结合结构域相邻的α螺旋D相关的PAI-1区域中。PAI-1上的肝素结合结构域的位置也已确定。所述位点也位于与抗凝血酶III的肝素结合域同源的区域中的α螺旋D,并且可能与LDL-R家族成员的结合位点重叠。
玻连蛋白在血浆中循环并存在于主要处于损伤或重构部位处的细胞外基质中。PAI-1和玻连蛋白似乎具有明显的功能互相依赖性。玻连蛋白稳定了PAI-1的活性构象,从而延长其生物学半衰期。
玻连蛋白还使PAI-1对凝血酶的抑制功效增强约300倍。继而,PAI-1与玻连蛋白的结合将其构象从不支持细胞粘附的原生血浆形式改变成具有结合整合素能力的“活化”形式。但是,整合素结合因PAI-1的存在而阻断。如上所述,PAI-1与玻连蛋白的缔合以构象方式受到控制,并且在抑制蛋白酶时,与RCL插入相关的PAI-1的构象变化导致损失对玻连蛋白的高亲和力并且获得对LDL-R家庭成员的亲和力。这是由于RCL插入到PAI-1中,破坏玻连蛋白结合位点,同时暴露仅当PAI-1与蛋白酶复合时才显露的隐藏受体结合位点,其导致PAI-1的相对亲和力以约100,000倍从玻连蛋白移位到LDL-R家族成员并且PAI-1的定位发生从玻连蛋白到细胞受体的后续移位。因此,PAI-1与玻连蛋白和LDL-R的缔合以构象方式受到控制。
高PAI-1水平与多种疾病和病症相关。例如,高PAI-1水平与急性疾病(如败血症和心肌梗塞)以及慢性病症(如癌症、动脉粥样硬化和2型糖尿病)相关。此外,高PAI-1水平与心血管疾病相关,其中PAI-1表达在严重的动脉粥样硬化血管中显著增加,并且PAI-1蛋白水平在疾病从正常血管进展到脂肪条纹到动脉粥样硬化斑块的过程中持续升高。PAI-1水平升高也与肥胖症和胰岛素抵抗有关。
另外,PAI-1的血浆水平升高与血栓形成事件相关,并且对PAI-1活性进行的抗体中和使得促成内源性血栓溶解和再灌注。PAI-1水平升高也与多囊性卵巢综合征和雌激素缺乏引起的骨质损失有关。
在鼠类和人类脂肪细胞中合成PAI-1。在人类和小鼠中,内脏脂肪量与PAI-1血浆水平之间也存在很强的相关性。肥胖症中PAI-1的这种急剧上调已表明:脂肪组织本身可能直接导致全身性PAI-1升高,继而通过增加血栓形成和加速动脉粥样硬化来增大血管疾病的几率。值得注意的是,最近的数据表明,PAI-1也可能在肥胖症中起直接作用。
在一项研究中,相较于具有PAI-1的ob/ob小鼠,处于PAI-1缺失背景中的遗传性肥胖和糖尿病性ob/ob小鼠体重显著降低并且代谢概况改善。同样,营养诱导的肥胖症和胰岛素抵抗在遗传上缺失PAI-1的小鼠和用口服活性PAI-1抑制剂处理的小鼠中也显著减弱。PAI-1缺失型小鼠的肥胖和胰岛素抵抗的改善可能与以下观察结果有关:相较于野生型小鼠,高脂肪膳食的PAI-1缺失型小鼠的代谢速率和总能量消耗增大,并且过氧化物酶体增殖物激活受体(PPARγ)和脂联素得以维持。然而,尚未显示所涉及的确切机制且其可能是复杂的,因为小鼠中PAI-1的过度表达也损害了脂肪组织的形成。综上所述,这些观察结果表明,PAI-1在肥胖症和胰岛素抵抗中起着之前未被认识到的直接作用,所述PAI-1参与的相互作用超出其已鉴别的调节纤维蛋白溶解和组织重构的活性。
实际上,如果PAI-1正向调节脂肪组织的发育,那么PAI-1表达增加与肥胖症发展的关联可能构成促进脂肪组织扩张和正常胆固醇平衡异常的正反馈回路。因此,本领域中需要对PAI-1如何参与代谢、肥胖症和胰岛素抵抗有更深入的理解。
发明内容
本文提供一种具有结构的化合物,其中X是Cl或F,或其药学上可接受的盐。在一些情况下,化合物是或其药学上可接受的盐。在一些情况下,化合物是或其药学上可接受的盐。还提供具有结构的PAI-1抑制剂或其药学上可接受的盐。进一步提供具有结构的PAI-1抑制剂或其药学上可接受的盐。在一些情况下,化合物呈药学上可接受的盐的形式。进一步提供本文所公开的一种或多种化合物或盐和药学上可接受的赋形剂的药物组合物。在一些情况下,组合物包含具有结构的化合物,或其药学上可接受的盐。在一些情况下,组合物包含具有结构的化合物,或其药学上可接受的盐。
进一步提供通过使PAI-1与本文所公开的化合物接触来抑制PAI-1的方法。还提供治疗与异常PAI-1活性相关的病症的方法,其包含以有效治疗病症的量向有需要的个体给予本文所公开的化合物。在一些情况下,病症是癌症、败血症、肥胖症、胰岛素抵抗、与脂质代谢异常相关的疾病或病症、与VLDL或LDL水平升高相关的疾病或病症、高胆固醇、增生性疾病或病症、纤维化和纤维化疾病、发炎性肠病、凝血平衡、脑血管疾病、微血管疾病、高血压、痴呆、动脉粥样硬化、骨质疏松、骨质减少、关节炎、哮喘、心力衰竭、心律失常、心绞痛、激素功能不全、阿尔茨海默病、高血压、炎症、败血症、纤维蛋白溶解性病症、中风、痴呆、冠心病、心肌梗塞、稳定型和不稳定型心绞痛、血管疾病、外围动脉疾病、急性血管综合征、血栓形成、血栓形成前、深静脉血栓形成、肺栓塞、脑血管疾病、微血管疾病、高血压、糖尿病、高血糖症、高胰岛素血症、恶性病变、癌前病变、胃肠道恶性肿瘤、脂肪肉瘤、上皮肿瘤和牛皮癣、细胞外基质累积病症、新血管生成、骨髓纤维化、纤维蛋白溶解性障碍、多囊性卵巢综合征、由雌激素缺乏引起的骨质损失、血管生成、新血管生成、骨髓纤维化或纤维蛋白溶解性障碍。在各种情况下,涉及血栓形成或血栓形成前的疾病或病症是动脉粥样硬化斑块的形成、静脉血栓形成、动脉血栓形成、心肌缺血、心房颤动、深静脉血栓形成、凝血综合征、肺血栓形成、脑血栓形成、手术的血栓栓塞性并发症和外围动脉闭塞。在一些情况下,病症是纤维化,并且更确切地说,可以是肺纤维化、肾纤维化、心脏纤维化、肝纤维化或硬皮病。在一些情况下,病症是发炎性肠病,并且更确切地说,可以是克隆氏病(Crohn's disease)或溃疡性结肠炎。在一些情况下,细胞外基质累积病症是肾纤维化、慢性阻塞性肺病、多囊性卵巢综合征、再狭窄、肾血管性疾病、糖尿病性肾病或器官移植排斥反应。
进一步提供调节PAI-1水平升高的个体的胆固醇、脂质清除和/或脂质摄取的方法,其包含向所述个体以有效降低个体的高水平PAI并且调节胆固醇、脂质清除和/或脂质摄取的量来给予有效量的本文所公开的化合物。在一些情况下,化合物增加个体的循环高密度脂蛋白(HDL)和/或降低循环极低密度脂蛋白(VLDL)。在各种情况下,化合物抑制载脂蛋白E(ApoE)或载脂蛋白A(ApoA)结合于VLDL-R。在各种情况下,化合物减少HDL或载脂蛋白E(ApoE)或载脂蛋白A(ApoA)结合于ApoA受体。在各种情况下,化合物减少PAI-1结合于载脂蛋白E(ApoE)。在各种情况下,化合物减少PAI-1结合于载脂蛋白A(ApoA)。在各种情况下,化合物减少PAI-1结合于VLDL。在各种情况下,化合物在玻连蛋白存在下结合于PAI-1。在各种情况下,化合物在尿激酶型纤维蛋白溶酶原活化物(uPA)存在下结合于PAI-1。
在本文所公开的任一种方法中,个体可以是人类。
前述发明内容并非旨在限定本发明的每个方面,并且在其它部分,如实施方式中描述了额外的方面。整个文档旨在作为统一的公开内容相关联,并且应理解,涵盖了本文所描述的特征的所有组合,即便特征的组合未在本文档的同一个句子或段落或部分中找到。
附图说明
图1展示了在各种浓度的CDE-517存在下的丝氨酸蛋白酶抑因子活性。
图2展示了在各种浓度的CDE-252存在下的丝氨酸蛋白酶抑因子活性。
图3展示了在各种浓度的CDE-519存在下的丝氨酸蛋白酶抑因子活性。
图4展示了在各种浓度的CDE-520存在下的丝氨酸蛋白酶抑因子活性。
图5展示了在各种浓度的CDE-264存在下的丝氨酸蛋白酶抑因子活性。
图6展示了在各种浓度的CDE-295存在下的丝氨酸蛋白酶抑因子活性。
图7展示了在各种浓度的CDE-234存在下的丝氨酸蛋白酶抑因子活性。
图8展示了在各种浓度的CDE-241存在下的丝氨酸蛋白酶抑因子活性。
图9展示了在各种浓度的CDE-246存在下的丝氨酸蛋白酶抑因子活性。
图10展示了在各种浓度的CDE-413存在下的丝氨酸蛋白酶抑因子活性。
图11展示了在各种浓度的CDE-415存在下的丝氨酸蛋白酶抑因子活性。
图12展示了在各种浓度的CDE-412存在下的丝氨酸蛋白酶抑因子活性。
图13展示了在各种浓度的CDE-248存在下的丝氨酸蛋白酶抑因子活性。
图14展示了在各种浓度的CDE-266存在下的丝氨酸蛋白酶抑因子活性。
图15展示了在各种浓度的CDE-301存在下的丝氨酸蛋白酶抑因子活性。
图16展示了在各种浓度的CDE-307存在下的丝氨酸蛋白酶抑因子活性。
图17展示了在各种浓度的CDE-340存在下的丝氨酸蛋白酶抑因子活性。
图18展示了在各种浓度的CDE-422存在下的丝氨酸蛋白酶抑因子活性。
图19展示了在各种浓度的CDE-423存在下的丝氨酸蛋白酶抑因子活性。
图20展示了在各种浓度的CDE-424存在下的丝氨酸蛋白酶抑因子活性。
图21展示了在各种浓度的CDE-446存在下的丝氨酸蛋白酶抑因子活性。
具体实施方式
本文提供一种具有结构的PAI-1抑制剂,其中X是Cl或F,或其药学上可接受的盐。在一些情况下,化合物具有结构或其药学上可接受的盐。在一些情况下,化合物具有结构或其药学上可接受的盐。进一步提供具有结构的PAI-1抑制剂或其药学上可接受的盐。进一步提供具有结构的PAI-1抑制剂或其药学上可接受的盐。还提供包含一种或多种这些化合物或其盐的药物组合物。
如本文所用,术语“药学上可接受的盐”是指在合理医学判断范围内适用于与人类和低等动物的组织接触而无不当毒性、刺激、过敏反应等,并且与合理的效益/风险比相当的那些盐。药学上可接受的盐在本领域中众所周知。举例来说,S.M.Berge等人在《医药科学杂志(J.Pharmaceutical Sciences)》,1977,66,1-19中详细描述了药学上可接受的盐,所述文献通过引用并入本文中。本公开的化合物的药学上可接受的盐包括由合适的无机和有机酸和碱衍生的盐。药学上可接受的无毒酸加成盐的实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸以及高氯酸)或与有机酸(如乙酸、三氟乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸)形成的盐,或通过使用本领域中所用的其它方法(如离子交换法)形成的盐。其它药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙烷磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、丁二酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。含有羧酸或其它酸性官能团的化合物的盐可以通过与合适的碱反应来制备。这类盐包括(但不限于)碱金属、碱土金属、铝盐、铵、N+(C1-4烷基)4盐和有机碱的盐,所述有机碱如三甲胺、三乙胺、吗啉、吡啶、哌啶、甲基吡啶、二环己胺、N,N'-二苯甲基乙二胺、2-羟乙胺、双-(2-羟乙基)胺、三-(2-羟乙基)胺、普鲁卡因、二苯甲基哌啶、脱氢松香胺、N,N'-双脱氢松香胺、还原葡糖胺、N-甲基葡糖胺、三甲基吡啶、奎宁、喹啉和碱性氨基酸,如赖氨酸和精氨酸。本公开还预想了在本文所公开的化合物的任何碱性含氮基团的季铵化。可以通过这种季铵化来获得水或油溶性或可分散性产物。代表性的碱金属盐或碱土金属盐包括钠、锂、钾、钙、镁等。适当时,其它药学上可接受的盐包括使用如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根以及芳基磺酸根等平衡离子形成的无毒铵、季铵以及胺阳离子。
使用PAI-1抑制剂的方法
如上所述,预期本文所公开的方法包括治疗与PAI-1水平升高相关的疾病或病症,其包含给予PAI-1抑制剂。在一个方面,个体是哺乳动物。在一些情况下,哺乳动物个体是人类。
在一些实施例中,本文提供PAI-1抑制剂化合物和使用所述化合物治疗与PAI-1活性相关的许多疾病或病症的方法。这类病状(例如疾病或病症)包括(但不限于)脂质代谢异常、肥胖症、糖尿病、多囊性卵巢综合征、由雌激素缺乏引起的骨质损失、纤维化和纤维化疾病、炎症、细胞迁移和迁移驱动的细胞增殖、血管生成和血栓形成。在一些方面,还预期这类抑制剂适用于调节内源性纤维蛋白溶解,并且与药理学血栓溶解结合。在各种方面,本文提供PAI-1抑制剂化合物和使用所述化合物治疗与高PAI-1水平(相较于已知未患有败血症、心肌梗塞或血栓形成的正常个体的PAI-1水平)相关的急性疾病的方法,所述急性疾病例如(但不限于)败血症、心肌梗塞和血栓形成。在一些方面,将本文所公开的PAI-1抑制剂化合物用于治疗与高PAI-1水平(相较于已知未患有以下这些疾病或病症的正常个体的PAI-1水平)相关的疾病和病症的方法中,所述疾病和病症例如(但不限于)癌症、动脉粥样硬化、胰岛素抵抗、2型糖尿病和纤维化疾病。在各种方面,本文提供用于调节脂质代谢的PAI-1抑制剂化合物,所述调节脂质代谢包括增加个体的循环HDL和/或降低循环VLDL。
在各种方面,PAI-1抑制剂可用于治疗其中降低PAI-1水平将提供益处的任何病状,包括疾病或病症PAI-1抑制剂可单独或与其它化合物组合使用,所述其它化合物可起到促进PAI-1水平降低的作用。
可将PAI-1抑制剂调配成适当的制剂,并以治疗有效量向个体内的一个或多个位点进行给药。在一些实施例中,基于PAI-1抑制剂的疗法通过连续或间歇静脉内给药来实现。在各种方面,基于PAI-1抑制剂的疗法通过连续或间歇肌肉内或皮下给药来实现。在其它方面,基于PAI抑制剂的疗法通过经口或经颊给药来实现。“有效量”是指足以支持PAI-1、纤维蛋白溶酶原活化物、HDL、LDL或VLDL的一种或多种生物活性水平的可观测变化和/或治疗方法旨在针对的适应症的可观测变化的PAI-1抑制剂化合物的量。所述变化可以是PAI-1活性水平降低。在一些方面,所述变化为纤维蛋白溶酶原活化物和/或HDL增加和/或LDL和VLDL减少。
在各种方面,对组合物的给药是全身性或局部的,并且在再其它方面,包含单位点注射治疗有效量的PAI-1抑制剂组合物。涵盖本领域的技术人员已知的用于给予本文所公开的治疗性组合物的任何途径,包括例如静脉内、肌肉内、皮下、经口或用于长期给药的导管。
在一些情况下,预期将治疗性组合物在多个位点向患者递送。可同时进行多次给药或在数小时内进行多次给药。同样预期治疗性组合物通过经口给药定期摄入。在某些情况下,提供治疗性组合物的连续流是有益的。定期(例如每天、每周或每月)给予额外疗法。
除仅基于PAI-1抑制剂组合物的递送的疗法之外,特别涵盖组合疗法。预期PAI-1抑制剂组合物疗法以与通常用于治疗PAI-1、LDL和VLDL水平升高的其它药剂结合的方式类似地使用。
为了实现适当的治疗结果,使用本文所公开的方法和组合物,进一步预期向有需要的个体给予包含PAI-1抑制剂和至少一种其它治疗剂(第二治疗剂)的组合物。这类治疗剂包括用于控制心血管疾病的药物,包括(但不限于)降低胆固醇的药物,如他汀类药物、抗炎剂和ACE抑制剂。这类药物还包括靶向神经病症的药物,包括(但不限于)用于靶向中风、癫痫和阿尔茨海默病的药物。在另一个方面,额外药剂包括(但不限于)靶向糖尿病的药物。这些都是与PAI-1水平升高相关的病症,并且因此预期组合疗法可与PAI-1抑制剂和其它已知疗法一起使用。
以在对PAI-1、VLDL或LDL的水平升高进行的治疗中有效产生所期望治疗结果和/或在本文所述的适应症中有效产生可检测变化的组合量来提供组合疗法组合物。这一方法涉及同时给予PAI-1抑制剂和一种或多种第二药剂或因子。因此,方法包括给予包括两种药剂的单一组合物或药理学调配物或同时给予两种不同组合物或调配物,其中一种组合物包括PAI-1抑制剂治疗性组合物并且另一种包括第二治疗剂。
或者,PAI-1抑制剂治疗在第二治疗剂治疗之前或之后,其时间间隔在几分钟到几周范围内。在将第二治疗剂与PAI-1抑制剂分开进行给药的实施例中,通常确保每次递送之间的相当长的时间并未到期,使得第二治疗剂与PAI-1抑制剂能够发挥有利的组合作用。在这类情况下,预期在彼此约12至24小时之内,或替代地在彼此约6至12小时之内,或替代地以仅约12小时的延迟时间给予两种模态。在一些情况下,需要显著地延长治疗时间段;然而,其中在每次给药之间经过数天(2、3、4、5、6或7)到数周(1、2、3、4、5、6、7或8)。
向患者全身性递送PAI-1抑制剂是用于递送治疗有效量的化合物以抵消疾病或病症的即时临床表现的极有效方法。或者,对PAI-1抑制剂和/或第二治疗剂的局部递送在某些情形下是适当的。在某一实施例中,预期将PAI-1抑制剂在一段延长的时间内向患者递送。进一步预期,在患者的整个生存期中摄取PAI-1抑制剂以降低PAI-1、VLDL和/或LDL水平。
药物组合物
如上所述,本文提供使用药物组合物的方法,所述药物组合物包含有效量的PAI-1抑制剂以及药学上可接受的赋形剂,如可用于PAI-1抑制剂疗法的稀释剂、防腐剂、增溶剂、乳化剂、佐剂和/或载剂。这类组合物包括各种缓冲剂内含物(例如Tris-HCl、乙酸盐、磷酸盐)、pH和离子强度的稀释剂;添加剂,如清洁剂和增溶剂(例如吐温(Tween)80、聚山梨醇酯80)、抗氧化剂(例如抗坏血酸、偏亚硫酸氢钠)、防腐剂(例如硫柳汞、苯甲醇)和增积物质(例如乳糖、甘露糖醇);将材料并入到聚合化合物(如聚乳酸、聚乙醇酸等)的微粒制剂中,或与脂质体或胶束缔合。这类组合物将影响PAI-1抑制剂的物理状态、稳定性、活体内释放速率和活体内清除速率。参见例如《雷明顿药物科学(Remington's PharmaceuticalSciences)》,第18版。(1990)Mack Publishing Co.,宾夕法尼亚州伊斯顿(Easton,PA),第1435-1712页,其以引用的方式并入本文中。
无菌液体组合物包括溶液、悬浮液、乳液、糖浆和酏剂。本文所公开的化合物可溶解或悬浮于药学上可接受的载剂中,如无菌水、无菌有机溶剂或两者的混合物。在一个方面,液体载剂适用于亲本注射。在化合物足够可溶的情况下,其可在使用或不使用合适的有机溶剂(如丙二醇或聚乙二醇)的情况下直接溶解于标准生理食盐水。必要时,细粉状化合物的分散液可在淀粉或羧甲基纤维素钠水溶液或合适的油(如花生油)中制备。可通过肌肉内、腹膜内或皮下注射来使用无菌溶液或悬浮液形式的液体药物组合物。在许多情况下,可使用液体组合物形式代替优选的固体经口给药法。
优选的是制备用于标准给药方案的化合物的单位剂型。以此方式,组合物可容易地按照医生的指示细分成较小剂量。举例来说,单位剂量可制成包装的散剂、小瓶或安瓿,并且在一个方面,制成胶囊或片剂形式。对于单次或多次每日给药,根据患者的特殊需求,存在于这些组合物单位剂型中的活性化合物的存在量可以是约一克到约十五克或更多。活性化合物的每日剂量将视给药途径、患者体型、年龄和性别、疾病病况的严重程度以及由血液分析和患者恢复速率所追踪的治疗反应而变化。
待使用的精确剂量取决于若干因素,包括宿主(不管是在兽医学或人类医学中)、所治疗的病状(例如疾病或病症)的性质和严重程度、给药模式和所使用的特定活性物质。化合物可通过任何常规途径,确切地说经肠,并且在一个方面,以片剂或胶囊形式经口进行给药。所给予的化合物可适当地呈游离形式或药学上可接受的盐形式,用作药物,确切地说用于预防性或治愈性治疗动脉粥样硬化和后遗症(心绞痛、心肌梗塞、心律失常、心力衰竭、肾衰竭、中风、外围动脉闭塞和相关疾病病况)。这些措施将减缓疾病病况的进展速率并辅助身体以自然方式逆转进展方向。
如本领域的技术人员将认识到,PAI-1抑制剂或其衍生物可被调配成用于注射或经口、经鼻、经肺、局部或其它类型的给药。调配物可以是液体或可以是用于复原的固体(如冻干的固体)。
PAI-1抑制剂或其衍生物适用于治疗与PAI-1、LDL或VLDL水平升高相关的急性或慢性疾病或病症中的任一种。在一些方面,通过给予PAI-1抑制剂缓解或调节的病状(例如疾病或病症)为特征在于VLDL和LDL水平升高的病状。这类病状可能随着出于其它目的进行的疗法过程(如化学疗法或辐射疗法)而被诱导。预期这类病状可由遗传产生或是另一种病状或药物的副作用。
短语“药学上或药理学上可接受的”是指当向动物或人给药时,分子实体和组合物不产生不利、过敏或其它不良反应。如本文所用,“药学上可接受的载剂”包括任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等张剂以及吸收延迟剂等。这类介质和试剂用于药学上活性物质的用途是本领域中已知的。除非任何常规介质或药剂与载体或细胞不相容,涵盖其在治疗组合物中的用途。也可将补充性活性成分并入到组合物中。
本文所公开的方法中使用的活性组合物包括传统药物制剂。这些组合物的给药将通过任何常用途径进行,只要可通过所述途径进入目标组织即可。药物组合物可通过任何常规方法引入到个体中,例如通过静脉内、皮内、肌肉内、乳房内、腹膜内、鞘内、眼球后、肺内(例如定期释放);通过经口、舌下、经鼻、肛门、阴道或经皮递送,或通过在特定部位处的手术植入。治疗可由单次给药或在一段时间内的多次给药组成。
活性化合物可以在适当地与表面活性剂(例如羟丙基纤维素)混合的水中制备为游离碱或药理学上可接受的盐的溶液以用于给药。分散液也可在甘油、液体聚乙二醇及其混合物中和油中制备。在存储和使用的一般条件下,这些制剂含有防腐剂,以预防微生物生长。
适用于可注射使用的药物形式包括无菌水溶液或分散液和用于临时制备无菌可注射溶液或分散液的无菌散剂。在所有情况下,所述形式必须是无菌的并且必须以易于注射的程度流动。在制造和储存条件下必须稳定,并且必须防止微生物体,如细菌和真菌的污染作用。载剂可以是含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)、其合适的混合物和植物油的溶剂或分散介质。可以例如通过使用包衣(如卵磷脂)在分散液情况下通过维持所需粒径和通过使用表面活性剂来维持适当的流动性。微生物作用的预防可通过各种抗细菌剂和抗真菌剂(例如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)来实现。在许多情况下,优选的是包含等张剂,例如糖或氯化钠。通过在组合物中使用延迟吸收剂(例如单硬脂酸铝和明胶),可实现可注射组合物的延长吸收。
根据需要,通过将活性组合物以所需量并入具有上文所列举的多种其它成分的适当溶剂中,接着过滤灭菌,以制备无菌可注射溶液。通常,通过将各种经过灭菌的活性成分并入无菌媒介物中来制备分散液,所述无菌媒介物含有基础分散介质和来自上面列举的那些的所需其它成分。在用于制备无菌可注射溶液的无菌散剂的情况下,优选的制备方法是真空干燥和冷冻干燥技术,其产生活性成分加上来自其先前无菌过滤溶液的任何额外期望成分的散剂。
如本文所用,“药学上可接受的载剂”包括任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等张剂以及吸收延迟剂等。这类介质和试剂用于药学上活性物质的用途是本领域中已知的。除非任何常规介质或药剂与活性成分不相容,涵盖其在治疗组合物中的用途。也可将补充性活性成分并入到组合物中。
对于组合物的经口给药,可将PAI-1抑制剂与赋形剂一起并入,并以不可摄取的漱口剂和洁牙剂的形式使用。可将活性成分按所需量并入适当溶剂(如硼酸钠溶液(Dobell氏溶液)中来制备漱口剂。或者,可将活性成分并入到含有硼酸钠、丙三醇和碳酸氢钾的水洗型抗菌剂中。还可将活性成分分散于洁牙剂中,所述洁牙剂包括凝胶、糊剂、散剂和浆料。可将活性成分以治疗有效量添加到可包括水、粘合剂、磨料、调味剂、发泡剂和保湿剂的糊剂洁牙剂中。
可将所述方法中使用的组合物调配成中性或盐形式。药学上可接受的盐包括酸加成盐(与蛋白的自由氨基形成),并且其是与无机酸(例如盐酸或磷酸)或有机酸(如乙酸、乙二酸、酒石酸、扁桃酸等)形成的酸加成盐。与自由羧基形成的盐还可由无机碱和有机碱衍生,所述无机碱例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁;所述有机碱例如异丙胺、三甲胺、组氨酸、普鲁卡因等。
可将所述方法中使用的组合物调配成胶束或脂质体。这种调配物包括空间稳定胶束或脂质体和空间稳定混合胶束或脂质体。这类调配物可有助于细胞内递送,因为已知脂质体和胶束的脂质双层与细胞的质膜融合且将所截留内含物递送到细胞内隔室中。
调配时,溶液将以与剂量调配物相容的方式和以例如治疗有效的量进行给药。调配物易于以多种剂型进行给药,如可注射溶液、药物释放胶囊等。例如,对于在水溶液中的肠胃外给药,必要时应对溶液进行适当缓冲,并且首先用足够生理食盐水或葡糖使液体稀释剂呈现等张。这些特定水溶液尤其适用于静脉内、肌肉内、皮下和腹膜内给药。
通常PAI-1抑制剂或其衍生物的有效量将由接受者的年龄、体重和病状或疾病或病症的严重程度确定。参见上文的《雷明顿药物科学(Remington's PharmaceuticalSciences)》,第697-773页,其以引用的方式并入本文中。通常,可使用介于约0.001微克/千克体重/天到约1000微克/千克体重/天之间的剂量,但可使用如技术人员将认可的更多或更少的剂量。给药可以是每日一次或多次,或较低频率,并且可与如本文所述的其它组合物结合。应注意,本公开不限于本文所述的剂量。
通过以约一克的最小每日剂量起始治疗方案,可使用PAI-1血液水平和患者的症状缓解分析来确定是否需要更大剂量。本领域的技术人员将了解,用于治疗的适当剂量水平将因此部分视递送的分子、正在使用的PAI-1抑制剂化合物的适应症、给药途径和患者的体型(体重、体表或器官大小)和病状(年龄和一般健康状况)而变化。因此,临床医师可滴定剂量并且可调整给药途径以获得最优治疗效果。取决于上文所提及的因素,典型剂量可在约0.1μg/kg到约100mg/kg或更高的范围内。在其它实施例中,所述剂量可在0.1μg/kg到约100mg/kg;或1μg/kg到约100mg/kg;或5μg/kg到约100mg/kg范围内。
“单位剂量”定义为分散于合适的载剂中的治疗性组合物的离散量。肠胃外给药可先推注进行,接着连续输注以维持药品的治疗性循环水平。本领域的一般技术人员将易于优化如由个别患者的良好医疗实践和临床病状确定的有效剂量和给药方案。
给药频率将取决于药剂的药物动力学参数和给药途径。根据给药途径和所期望的剂量,本领域的技术人员将确定最优药物调配物。参见例如上文的《雷明顿药物科学(Remington's Pharmaceutical Sciences)》,第1435-1712页,其以引用的方式并入本文中。这类调配物可能影响所给予的药剂的物理状态、稳定性、活体内释放速率和活体内清除速率。取决于给药途径,可根据体重、体表面积或器官大小计算合适的剂量。本领域的一般技术人员在无需过度实验的情况下即可常规地进行对确定适当治疗剂量所需的计算的进一步优化,尤其根据本文所公开的剂量信息和分析,以及在动物或人类临床试验中观察到的药物动力学数据。
可通过使用所建立的分析来确定适当剂量,所述分析结合相关剂量反应数据测定心肌梗塞水平。最终剂量方案将由主治医生在考虑改变药物作用的多种因素的情况下确定,所述因素例如药物的比活性、损伤的严重程度和患者的反应性、患者的年龄、条件、体重、性别以及膳食、任何感染的严重程度、给药时间以及其它临床因素。当进行研究时,将出现关于适当剂量水平和治疗持续时间的更多信息。
应了解,本文所公开的药物组合物和治疗方法适用于人类医学和兽医学领域。因此,在一个方面,待治疗的个体为哺乳动物。在另一个方面,哺乳动物为人类。
另外,进一步涵盖一种试剂盒,其所含有的组分包含有包含PAI-1抑制剂的组合物;和任选地,至少一种适用于治疗本文所论述的急性和慢性疾病和病症的额外因子。
化合物在治疗疾病或病症中的用途
本文提供本文所公开的化合物的用途,其用于产生供治疗或预防本文所论述的任何疾病或病症用的药剂。
化合物为丝氨酸蛋白酶抑制因子PAI-1的抑制剂,并且因此可用于治疗或预防涉及PAI-1产生和/或作用的那些过程。因此,在各种方面中,如本文所述,化合物适用于预防或减少血栓形成、促进血栓溶解、减少纤维化,调节脂质代谢。在一些方面,化合物适用于治疗高胆固醇和与PAI-1水平升高相关的疾病或病症。在各种方面,所述化合物适用于治疗VLDL或LDL水平升高。在一些方面,化合物可用于升高HDL。
在一些方面,提供这些抑制剂用于治疗与PAI-1活性相关的疾病或病症中的用途。这类疾病或病症包括(但不限于)炎症、细胞迁移和迁移驱动的细胞增殖以及血管生成或血栓形成。还预期这类抑制剂适用于调节内源性纤维蛋白溶解,并且与药理学血栓溶解结合。
化合物适用于治疗或预防胰岛素抵抗、肥胖症、非胰岛素依赖性糖尿病、心血管疾病、与冠状动脉相关的血栓性事件和脑血管疾病。化合物还适用于抑制涉及血栓性和血栓前性状态的疾病过程,所述状态包括(但不限于)动脉粥样硬化斑块的形成、静脉和动脉血栓形成、心肌缺血、心房颤动、深静脉血栓形成、凝血综合征、肺血栓形成、脑血栓形成、手术(如关节置换术)的血栓栓塞性并发症和外围动脉闭塞。这些化合物还适用于治疗与心房颤动相关或由其产生的中风。
化合物还用于治疗或预防高胆固醇和与这一病状相关的疾病或病症。
化合物还可用于治疗与细胞外基质累积相关的疾病或病症,包括(但不限于)肾纤维化、慢性阻塞性肺病、多囊性卵巢综合征、再狭窄、肾血管性疾病和器官移植排斥反应。
化合物还可用于治疗纤维化,包括(但不限于)肺纤维化、肾纤维化、心脏纤维化、肝纤维化和硬皮病。
化合物还可用于治疗发炎性肠病,包括(但不限于)克隆氏病或溃疡性结肠炎。
化合物还可用于治疗恶性肿瘤和与新血管生成相关的疾病或病症(如糖尿病性视网膜病变)。
化合物还可与涉及维持血管开放的过程或程序结合并在其之后使用,所述过程或程序包括血管手术、血管移植和支架通畅、器官、组织和细胞植入和移植。
化合物还可用于治疗阿尔茨海默病。这一方法还可表征为在哺乳动物(确切地说,正在经历或经受阿尔茨海默病的人类)中PAI-1对纤维蛋白溶酶原活化物的抑制作用。这一方法还可表征为增加哺乳动物(确切地说,正在经历或经受阿尔茨海默病的那些动物)的纤维蛋白溶酶水平或使其正常化的方法。
化合物可用于通过调节基质细胞增生和增加细胞外基质蛋白来治疗骨髓纤维化伴随髓样化生。
化合物还可与含有蛋白酶抑制因子的高度活性抗逆转录病毒疗法(HAART)结合使用,以治疗来源于接受这种疗法的HIV-1感染患者的纤维蛋白溶解性障碍和高凝状态的疾病或病症。
化合物可用于治疗糖尿病性肾病和与肾病相关的肾透析。
化合物可用于治疗癌症、败血症、增生性疾病(如牛皮癣)、改善凝血平衡、脑血管疾病、微血管疾病、高血压、痴呆、动脉粥样硬化、骨质疏松、关节炎、哮喘、心力衰竭、心律失常、心绞痛,以及作为激素替代剂来治疗、预防或逆转动脉粥样硬化、阿尔茨海默病、骨质疏松、骨质减少症进展;减少发炎性标记物、纤维蛋白溶解性病症,降低C-反应蛋白,或预防或治疗低级血管炎症、中风、痴呆、冠心病、心肌梗塞的一级和二级预防、稳定型和不稳定型心绞痛、冠状动脉事件的一级预防、心血管事件的二级预防、外围血管疾病、外围动脉疾病、急性血管综合征、深静脉血栓形成、肺栓塞、降低经历心肌血管再生成过程的风险、微血管疾病(如肾病、神经病、视网膜病和肾病综合征)、高血压、1型和2型糖尿病及相关疾病、肥胖症、胰岛素抵抗、高血糖症、高胰岛素血症、恶性病变、癌前病变、胃肠道恶性肿瘤、脂肪肉瘤和上皮肿瘤、增生性疾病(如牛皮癣)、改善凝血平衡和/或改善内皮功能,以及所有形式的脑血管疾病。
本文所公开的化合物可用于伤口愈合中的局部施用以预防瘢痕。
本文所公开的化合物可用于治疗发炎性疾病、败血症性休克和与感染相关的血管损伤,并且用于处理用于透析、流体相中的血液存储,尤其是活体外血小板凝集的血液和血液产物。化合物还可与血栓溶解剂、纤维蛋白溶解剂和抗凝血剂组合使用。本发明化合物还可在医院环境中的血液化学物质的分析期间添加到人类血浆中,以测定其纤维蛋白溶解能力。
本文进一步提供用于治疗、预防、改善或抑制哺乳动物的(在一个方面为人类的)本文所提及的每种疾病的方法,所述方法各自包含向需要这种治疗、预防、改善或抑制的哺乳动物给予药学或治疗有效量的本文所公开的化合物或其药学上可接受的盐。
本文所公开的化合物还可用于治疗癌症,包括(但不限于)乳癌和卵巢癌,以及用作识别转移性癌症的成像剂。
应理解,本文化合物的药学或治疗有效量是指所讨论的化合物的以下量,所述量将在有需要的哺乳动物中充分抑制丝氨酸蛋白酶抑制因子PAI-1,以足够程度地提供所讨论的病状的所期望改善或提供对丝氨酸蛋白酶抑制因子PAI-1的充分抑制作用来预防、抑制或限制所讨论的疾病或病状的生理基础的发作。
实例
合成化合物CDE 517:
2-((4-氯-3-(三氟甲氧基)苯甲基)氨基)-2-氧代乙酸乙酯:在冰浴中冷却4-氯-3-(三氟甲氧基)苯甲胺(771.9mg,3.42mmol)和吡啶(830μL,10.26mmol)于二氯甲烷(10mL)中的搅拌溶液。逐滴添加乙基乙二酰氯(385μL,3.42mmol),并且在室温下搅拌混合物24小时。将反应混合物用乙酸乙酯稀释并用0.2N HCl(2×)、饱和NaHCO3水溶液(2×)和盐水(1×)洗涤。有机层经硫酸镁干燥,过滤,并且在真空中浓缩,得到呈透明油状的1.0726g产物(96%产率)。1H-NMR(DMSO-d6,400MHz)δ9.5(t,J=6Hz,1H),7.62(d,J=8.2Hz,1H),7.44(bs,1H),7.3(dd,J=8.7,1.8Hz,1H),4.33(d,J=6.4Hz,2H),4.21(q,J=6.9Hz,2H),1.23(t,J=6.9Hz,3H)。
N-(4-氯-3-(三氟甲氧基)苯甲基)-2-肼基-2-氧代乙酰胺(CDE-517):向2-((4-氯-3-(三氟甲氧基)苯甲基))氨基))-2-氧代乙酸乙酯(1.0726g,3.29mmol)于无水乙醇(30mL)中的溶液中逐滴添加50%水合肼(425μL,6.59mmol)并搅拌2小时。过滤固体,在真空中干燥,并且接着用沸腾去离子水湿磨,得到呈白色固体状的0.7191g产物(70.2%产率)。1H-NMR(DMSO-d6,400MHz)δ10.1(bs,1H),9.37(t,J=6.4Hz,1H),7.61(d,J=8.2Hz,1H),7.42(bs,1H),7.28(dd,J=8.3,1.8Hz,1H),4.5(d,J=3.6Hz,2H),4.31(d,J=6.4Hz,2H);13C-NMR(DMSO-d6,100MHz)δ160.6,158.3,144.3,141.1,131.4,128.5,124.8,122.4,120.6(q,J=256.5Hz),41.8。
合成化合物CDE-415:
N-(3-氯-4-氟苯甲基)-2-肼基-2-氧代乙酰胺(CDE-415):在冰浴中向3-氯-4-氟苯甲基胺(230μL,1.83mmol)和吡啶(296μL,3.66mmol)于二氯甲烷(5ml)中的溶液中逐滴添加2-氯-2-氧代乙酸乙酯(215μL,1.92mmol)。5分钟后从冰浴中移除溶液并且使其升温到室温。用乙酸乙酯稀释反应混合物,用0.2N HCl(2×)和饱和NaHCO3(1×)洗涤,用MgSO4干燥,过滤并在真空中浓缩,得到0.336g呈白色固体状的2-(3-氯-4-氟苯甲基氨基)-2-氧代乙酸乙酯(71%产率)。1H NMR(CDCl3,400MHz)(s,1H),7.34(dd,J=2.3,6.9Hz,1H),7.17(M,1H),7.10(t,J=8.7Hz,1H),4.46(d,J=6.0Hz,2H),4.35(q,J=7.3Hz,2H),1.39(t,J=6.9Hz,3H)。向2-(3-氯-4-氟苯甲基氨基)-2-氧代乙酸乙酯(211.9mg,0.816mmol)于乙醇(6ml)中的溶液中逐滴添加50%水合肼(102μL)。将反应物在室温下搅拌过夜。从混合物中过滤产物并在真空中干燥,得到0.188g呈白色固体状的N-(3-氯-4-氟苯甲基)-2-肼基-2-氧代乙酰胺(94%产率)。1H NMR(DMSO-d6,400MHz)(s,1H),9.28(t,J=6.4Hz,1H),7.42(dd,J=1.8,5.5Hz,1H),7.32(t,J=8.7Hz,1H),7.23(m,1H),4.48(s,2H),4.25(d,J=6.4Hz,2H);13C NMR(DMSO-d6,100MHz)158.43,156.75(d,J=244Hz),137.32,129.97,128.63,119.62(J=18Hz),117.25(J=20Hz),41.66。
合成化合物CDE-412:
N-(4-氯-3-氟苯甲基)-2-肼基-2-氧代乙酰胺(CDE-412):在冰浴中向4-氯-3-氟苯甲基胺(225μL,1.83mmol)和吡啶(296μL,3.66mmol)于二氯甲烷(5ml)中的溶液中逐滴添加2-氯-2-氧代乙酸乙酯(215μL,1.92mmol)。10分钟后从冰浴中移除溶液并且使其升温到室温。用乙酸乙酯稀释反应混合物,用0.2N HCl(2×)和饱和NaHCO3(1×)洗涤,用MgSO4干燥,过滤且在真空中浓缩,得到0.3878g呈白色固体状的2-(4-氯-3-氟苯甲基氨基)-2-氧代乙酸乙酯(82%产率)。1H NMR(CDCl3,400MHz)(s,1H),7.36(t,J=7.96Hz,1H),7.09(d,J=9.6Hz,1H),7.02(d,J=8.3Hz,1H),4.48(d,J=6.4Hz,2H),4.35(q,J=6.9Hz,2H),1.38(t,J=6.9Hz,3H)。向2-(4-氯-3-氟苯甲基氨基)-2-氧代乙酸乙酯(119.7mg,0.461mmol)于乙醇(6ml)中的溶液中逐滴添加50%水合肼(57μL)。将反应物在室温下搅拌过夜。从混合物中过滤产物并在真空中干燥,得到59.0mg的呈白色固体状的N-(4-氯-3-氟苯甲基)-2-肼基-2-氧代乙酰胺(52%产率)。1H NMR(DMSO-d6,400MHz)δ10.02(s,1H),9.30(t,J=6.4Hz,1H),7.49(t,J=8.24Hz,1H),7.24(dd,J=1.8,10.5Hz,1H),7.08(dd,J=1.36,8.24Hz,1H),4.51(s,2H),4.27(d,J=6.4Hz,2H);13C NMR(DMSO-d6,100MHz)158.74,158.40,156.29,141.29,141.23,130.99,125.08,125.05,118.36,118.19,116.31,116.10,41.86。
PAI-1抑制剂的荧光测定IC50板分析:为了分析血浆中的PAI-1抑制剂活性,将重组活性人类PAI-1(Molecular Innovations)添加到含有10μg/mL的抑肽酶(Roche)的PAI-1耗尽型人类血浆(Molecular Innovations)中,达到浓度为20nM。随后将10μL这一人类血浆(具有或不具有PAI-1)添加到含有80μL缓冲液的孔中,其中PAI-1抑制剂浓度逐渐增大(缓冲液:40mM HEPES,100mM NaCl,0.005%吐温20,pH为7.4,和10%DMSO)并在23℃下培育15分钟。接着,将10μL的25nM UPA(rheotromb)(最终2.5nM)添加到每个反应孔中并且在24℃下再培育30分钟,最终PAI-1浓度为2nM并且最终uPA浓度为2.5nM。在这一培育后,添加100μL含有100mM的uPA荧光底物Z-Gly-Gly-Arg-AMC(Calbiochem)的缓冲液,达到最终浓度为50μM,并且由uPA的AMC释放速率确定每种反应混合物中的残余uPA活性,所述释放速率在23℃下用370nm的激发波长和440nm的发射波长测量10分钟。将数据表示为残余PAI-1活性占对照PAI-1活性的百分比。
对于缓冲液或含有1.5%牛血清白蛋白(BSA)的缓冲液中的分析,所述分析与上相同,不同之处在于不添加血浆或抑肽酶,并且在100mM NaCl、40mM HEPES、0.005%吐温20、10%DMSO、pH为7.4或在含有1.5%BSA的相同缓冲液中测定活性。结果展示于图中。图1是结构的化合物(CDE-517)。图2是结构的化合物(CDE-252)。图3是结构的化合物(CDE-519)。图4是结构的化合物(CDE-520)。图5是结构的化合物(CDE-264)。图6是结构的化合物(CDE-295)。图7是结构的化合物(CDE-234)。图8是结构的化合物(CDE-241)。图9是结构的化合物(CDE-246)。图10是结构的化合物(CDE-413)。
图11是结构的化合物(CDE-415)。图12是结构的化合物(CDE-412)。将这些数据与单卤代苯基化合物CDE-248和CDE-266(分别是图13和14)以及各种其它二卤代苯基化合物的数据进行比较:(CDE-301,图15);(CDE-307,图16);(CDE-340,图17);(CDE-422,图18);(CDE-423,图19);(CDE-424,图20);和(CDE-446,图21)。
Claims (25)
1.一种具有以下结构的化合物:
或其药学上可接受的盐。
2.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于抑制纤维蛋白溶酶原活化物抑制因子-1(PAI-1)的药物中的用途。
3.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于治疗与异常PAI-1活性相关的病症的药物中的用途,其中所述与异常PAI-1活性相关的病症是癌症、败血症、肥胖症、胰岛素抵抗、高胆固醇、增生性疾病、纤维化、高血压、痴呆、动脉粥样硬化、骨质疏松、哮喘、心力衰竭、心律失常、激素功能不全、炎症、中风、冠心病、心肌梗塞、外围动脉疾病、急性血管综合征、血栓形成、糖尿病、高血糖症、高胰岛素血症、癌前病变、脂肪肉瘤、牛皮癣、细胞外基质累积病症、新血管生成、多囊性卵巢综合征、由雌激素缺乏引起的骨质损失或纤维蛋白溶解性病症。
4.根据权利要求3所述的用途,其中所述与异常PAI-1活性相关的病症是发炎性肠病、阿尔茨海默病或肺栓塞。
5.根据权利要求3所述的用途,其中所述与异常PAI-1活性相关的病症是关节炎、心绞痛、血管疾病、恶性病变、深静脉血栓形成或骨质减少。
6.根据权利要求5所述的用途,其中所述心绞痛是稳定型或不稳定型心绞痛。
7.根据权利要求3所述的用途,其中所述与异常PAI-1活性相关的病症是胃肠道恶性肿瘤。
8.根据权利要求3所述的用途,其中所述与异常PAI-1活性相关的病症是上皮肿瘤。
9.根据权利要求5所述的用途,其中所述血管疾病是脑血管疾病。
10.根据权利要求5所述的用途,其中所述血管疾病是微血管疾病。
11.根据权利要求3所述的用途,其中所述纤维蛋白溶解性病症是纤维蛋白溶解性障碍。
12.根据权利要求3所述的用途,其中所述与异常PAI-1活性相关的病症是动脉粥样硬化斑块的形成、静脉血栓形成、动脉血栓形成、心肌缺血、心房颤动、凝血综合征、肺血栓形成、脑血栓形成、手术的血栓栓塞性并发症或外围动脉闭塞。
13.根据权利要求3所述的用途,其中所述纤维化是肺纤维化、肾纤维化、心脏纤维化、肝纤维化、骨髓纤维化或硬皮病。
14.根据权利要求4所述的用途,其中所述发炎性肠病是克隆氏病或溃疡性结肠炎。
15.根据权利要求3所述的用途,其中所述细胞外基质累积病症是慢性阻塞性肺病、肾血管性疾病、糖尿病性肾病或器官移植排斥反应。
16.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于调节PAI-1水平升高的个体的胆固醇、脂质清除和/或脂质摄取的药物中的用途。
17.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐增加所述个体的循环高密度脂蛋白(HDL)和/或降低循环极低密度脂蛋白(VLDL)。
18.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐抑制载脂蛋白E(ApoE)或载脂蛋白A(ApoA)结合于VLDL-R。
19.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐减少HDL或载脂蛋白E(ApoE)或载脂蛋白A(ApoA)结合于ApoA受体。
20.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐减少PAI-1结合于载脂蛋白E(ApoE)。
21.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐减少PAI-1结合于载脂蛋白A(ApoA)。
22.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐减少PAI-1结合于VLDL。
23.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐在玻连蛋白(vitronectin)存在下结合于PAI-1。
24.根据权利要求16所述的用途,其中所述化合物或其药学上可接受的盐在尿激酶型纤维蛋白溶酶原活化物(uPA)存在下结合于PAI-1。
25.根据权利要求16到24中任一项所述的用途,其中所述个体是人类。
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EP3657946A4 (en) | 2021-04-07 |
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