CN103391766A - 用于治疗囊性纤维化的新的组合物 - Google Patents
用于治疗囊性纤维化的新的组合物 Download PDFInfo
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- CN103391766A CN103391766A CN2012800079328A CN201280007932A CN103391766A CN 103391766 A CN103391766 A CN 103391766A CN 2012800079328 A CN2012800079328 A CN 2012800079328A CN 201280007932 A CN201280007932 A CN 201280007932A CN 103391766 A CN103391766 A CN 103391766A
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Abstract
本发明提供了用于通过选择性增加支气管上皮细胞中的cAMP水平来预防或者治疗囊性纤维化的组合物,其包含至少一种前列环素或者前列环素类似物或者其药用盐以及至少一种磷酸二酯酶(PDE)4抑制剂和任选地另外的PDE抑制剂。
Description
技术领域
本发明提供了用于预防或者治疗囊性纤维化的组合物,其包含前列环素或者前列环素类似物与磷酸二酯酶抑制剂4的组合,以及提供了具体组合物。
背景技术
前列腺素I2(前列环素;依前列醇,PGI2)为通过环氧合酶和PGI合酶的连续活性所酶性形成的花生四烯酸的氧化代谢产物。其在构成上由血管内皮和平滑肌细胞产生且在血管细胞和巨噬细胞中在炎性条件下诱导。
PGI2为有效的血管舒张和抗凝血剂,其作用由与独特的七螺旋G蛋白偶联受体(称为I类前列腺素(IP)4受体)结合所导致。该受体与Gs-偶联且活化腺苷酸环化酶,这导致细胞内cAMP的急速增长。由于CFTR和突变的CFTR的表达是cAMP-依赖性的,所以增强细胞内cAMP水平的物质是开发用于治疗CF的药物所感兴趣的。然而,这些物质中的大多数诸如福斯高林诱导了cAMP相当程度的非特异性的提升,这也可具有非常有害的作用诸如炎症。因此,存在对于肺上皮细胞中cAMP的特异性增强剂的尚未满足的需求。
曲前列素(Treprostinil)为有效的IP受体激动剂,尽管其对于该受体的特异性是未知的。Sprague R.S.et al.,Microcirculation2008Jul;15(5):461-71显示了前列环素类似物(UT-15,Remodulin)刺激受体介导的cAMP合成以及ATP由兔和人红细胞的释放。
细胞核磷酸二酯酶(PDE)为催化cAMP和环状3′,5-单磷酸鸟苷(cGMP)水解为无活性的5′-核苷酸产物的酶。cAMP和cGMP展现出许多细胞内作用,其大部分由它们对多底物蛋白激酶的刺激作用所介导。通过抑制PDE,cAMP和cGMP的水平增加,这导致气道平滑肌的舒张以及炎症细胞活化的抑制。PDE4、PDE7和PDE8对于cAMP是特异性的。
磷酸二酯酶抑制剂阻断一种或者多种磷酸二酯酶(PDE)的亚型,因此防止细胞内第二信使环磷腺苷(cAMP)和环磷鸟苷(cGMP)由它们各自的PDE亚型的失活。环状-3′,5′-核苷酸PDE的同工酶为cAMP蛋白激酶A(PKA)信号传导途径的至关重要的组分。已经鉴定了11种PDE家族。同工酶的超家族由至少九个基因家族(类型)PDE1至PDE11构成。一些PDE家族是非常多样化的且由若干亚型和众多同工型剪接变体构成。
非特异性PDE抑制剂的实例为茶碱和相关的黄嘌呤化合物、咖啡因、氨茶碱等。长春西丁为PDE1选择性抑制剂。已知的PDE2选择性抑制剂为EHNA或者阿那格雷,PDE3选择性抑制剂为依诺昔酮或者米力农。
PDE4为出现于炎症和免疫细胞中的主要的cAMP-代谢酶。已经证实了PDE4抑制剂作为抗炎药物的潜能,特别是对于炎性肺病诸如哮喘、COPD和鼻炎的潜能。它们抑制细胞因子和其它炎症信号的释放,且抑制活性氧簇的产生。已知的PDE4抑制剂为例如松叶菊碱、咯利普兰、异丁司特等。
PDE5抑制剂主要由细胞色素P450酶CYP3A4代谢。对于与抑制或者诱导CYP3A4的其它药物(包括HIV蛋白酶抑制剂、酮康唑、伊曲康唑和其它抗高血压药物诸如Nitro-喷雾剂)的不良药物相互作用存在所述潜能。PDE5抑制剂的实例为西地那非、他达那非、伐地那非或者优地那非。
囊性纤维化(CF)是第7号染色体上一个230kb的基因的突变所导致的遗传疾病,该基因编码被称为囊性纤维化跨膜传导调节因子(CFTR)的含有1480个氨基酸的多肽,该多肽在表皮细胞膜中发挥氯离子通道的作用。迄今已鉴别了1000多个等位基因突变体。最常见的突变ΔF508是囊性纤维化跨膜传导调节因子(CFTR)蛋白中密码子508处苯丙氨酸残基的缺失。该突变导致CFTR功能严重下降,且造成典型的囊性纤维化表型,其特征在于外分泌腺功能的异常,比如汗液氯化物增加、反复的呼吸道感染并伴有支气管扩张症,以及早发型胰功能不全。
临床上,当个体中出现一个或多个典型的CF表型特征时,通常会怀疑是CF。这可能是单独的慢性肺病或者往往与胃肠和营养异常(例如胰功能不全和复发性胰腺炎)、盐耗综合征(salt loss syndrome)和男性泌尿生殖系统异常(即阻塞性无精症)相关。在人的肺中,浓厚粘稠的分泌物堵塞了远端呼吸道和表达CFTR的粘膜下腺体。这些腺体的导管扩张(与粘液的阻塞相关)和呼吸道表面被浓厚粘稠的、主要是嗜中性粒细胞的脓性碎片覆盖是疾病的病理标志。肺部炎症是囊性纤维化受试者中呼吸功能衰退的另一个主要成因,且可能在慢性感染开始之前发生。胰管内的粘液嵌塞和粘稠凝结在先前被诊断为原发性或者酒精性胰腺炎的受试者亚群中造成慢性纤维化、腺体的脂肪替代或者两种情况均有。
囊性纤维化是高加索人群体中最常见的致死性遗传疾病,一万名儿童中有大约4名受其影响。在美国,死亡的中值年龄从1969年的8.4岁提高到1998年的14.3岁。死亡的平均年龄从1969年的14岁提高到2003年的32.4岁(Cystic Fibrosis Foundation)。对出生在1990年代的儿童,存活年龄中值预计将超过40岁。预期寿命显著延长的主要因素是对CF受试者中慢性呼吸道感染的治疗和粘液清除的改善,以及营养状况的改善和更早诊断。
呼吸道上皮细胞顶膜失去囊性纤维化跨膜传导调节因子(CFTR)阴离子传导会破坏呼吸道表面液体层的调节。这导致囊性纤维化(CF)特征性的粘液纤毛清除功能受损、呼吸道感染和炎症。常见的CFTRΔF508突变在90%以上的CF患者中存在于至少一个等位基因中,且在50%以上患者中是ΔF508纯合的,其余的是复合杂合子。CF疾病的一个重要问题是这种常见CFTR变体不能实现天然折叠态,所述折叠态离开内质网(ER)并被输送到上皮细胞顶膜。
如果天然构象的形成受到阻碍,CFTR被认为与分子伴侣保持过多或过长的相互作用,而这又会使该蛋白成为ER中负责管理那些错折叠或未完全复合的蛋白的降解机制的靶标。ER-相关降解(ERAD)包括异常蛋白的泛素化和它们被运送到蛋白酶体进行降解。如果ERAD落后于蛋白合成的速度,或者在使用蛋白酶体抑制剂进行治疗的过程中,突变蛋白的聚集物将逐渐累积。CFTR是第一个经鉴定是泛素-蛋白酶体介导的降解的底物的哺乳动物整合膜蛋白,一直作为日益增加的病理病因学非常多样性的蛋白质构象疾病的模型。
基本上细胞产生的所有ΔF508CFTR被ERAD破坏。并且,由于其折叠方式的复杂,60-70%的野生型(wt)蛋白也被类似地降解,虽然这在不同细胞类型之间有差别。不成熟形式的wt和ΔF508CFTR的溶蛋白性裂解方式相似,而成熟wt CFTR有不同的消化方式。这一发现支持了截留ER的突变CFTR中至少有一部分处于沿着正常CFTR折叠途径形成的中间构象的观点,而不是形成了变异体蛋白结构。对于ΔF508CFTR,该中间构象不能越过折叠过程中的某个关键步骤,但它意味着如果能够协助这个步骤,ΔF508CFTR有可能得以挽救。
诸如降低温度、与化学伴侣分子或者药物校正剂共同孵育的多种试验条件可以促使ΔF508CFTR逃离ER,在细胞表面形成功能性阴离子通道。此外,研究人员曾报道通过共表达各种部分CFTR构建体或wt CFTR的亚结构域能够恢复ΔF508CFTR的功能。但是,对于能够有效拯救突变蛋白的CFTR亚结构域没有明显的一致认知,这一效果的机制仍不清楚。并且,CFTR片段诱导的拯救主要是在同时外源性过表达CFTR片段和全长ΔF508CFTR的细胞中观察到的。
WO08/098196描述了利用曲前列素治疗肺纤维化。但是肺纤维化是由肺中胶原蛋白纤维累积导致的间质肺疾病;肺吸入空气的能力受到限制:肺失去了顺应性,气道阻力增加(顺应性=1/阻力)。随着疾病发展,血管阻力也增加。曲前列素对肺纤维化的作用部位是脉管系统和肺泡中的间隙。
Tissieres等描述了利用伊洛前列素治疗患有囊性纤维化和继发性肺动脉高压的患者。据公开吸入的伊洛前列素能够有效降低肺动脉压(The annalsof thoracic surgery,vol,78,no.3,E48-E50)。
US2001/006979A1描述了利用前列环素衍生物,比如伊洛前列素或西卡前列素治疗纤维化疾病。
囊性纤维化与肺纤维化无关,因为前者是始于支气管上皮的疾病。由于缺乏CFTR,覆盖支气管上皮的粘液中水分太少,因此纤毛无法移动粘稠的粘液,粘膜纤毛清除被破坏(粘膜纤毛清除与传送带工作方式类似,纤毛以集中的方式有节奏地摆动从而将粘液送回到气管和咽喉,从这些地方再通过吞咽或咳嗽等被清除)。如果粘膜纤毛清除被破坏,细菌不能被从支气管除去,则支气管被细菌占据,肺部感染反复发作使肺受到损害。这种情况可以通过恢复支气管上皮的Cl-流得以补救。因此,在囊性纤维化中作用部位是支气管的气道上皮。作用部位在解剖学上是不同的(肺间质vs.支气管气道),涉及不同的细胞群(纤维母细胞、血管平滑肌细胞、内皮细胞vs.吸收和分泌性的支气管上皮细胞)并且估计涉及的受体也不同(前列环素受体相比于可能的EP2-受体)。
DE102005016345A1和US2005101608A1描述了PDE5抑制剂在治疗肺动脉高压中的用途。
US2009325976A1公开了新的前列环素衍生物,其也可与PDE5抑制剂组合使用以用于治疗肺高动脉压。
针对在低cAMP水平情况下激活氯的分泌来测试临床使用的PDE抑制剂,如Cobb B.R.et al.,(Am J Respir Cell Mol Biol.2003Sep;29(3Pt1):410-418)所描述。
PDE5抑制剂昔多芬和伐地那非以及它们在囊性纤维化中的氯转运中的作用由Lubamba B.Et al.(Am J RespirCrit Care Med.2008Mar1;177(5):506-515)所描述。
PDE5抑制剂以及它们在ΔF508CFTR通道功能中的作用由Clarke LaneL.(J RespirCrit Care Med.2008Mar1;177(5):469-70)所描述。
在WO2010106494A1中公开了松叶菊碱HCl(已知的弱PDE4抑制剂)在治疗病症中的用途。
US20070249668描述了含有PDE抑制剂和前列环素类似物的组合物,其增加红血细胞中的ATP含量。
目前,没有能够长期显著提高患者生活质量的囊性纤维化疗法。因此本发明的一个目的是提供能增强肺上皮细胞内ΔF508CFTR的表达和/或氯通道功能的治疗组合物。
发明内容
本发明的目的通过提供包含至少一种前列环素或者类似物、衍生物或者其药用盐与至少一种PDE4抑制剂的组合的组合物来实现,所述组合物用于预防或者治疗囊性纤维化。作为可选择的实施方案,所述组合物可进一步包含至少一种PDE5和/或者PD7和/或者PDE8抑制剂。
具体地,所述前列环素类似物选自曲前列素、伊洛前列素、西卡前列素或者贝前列素(Beraprostor)或者它们的衍生物或者药用盐。在本发明的一个实施方案中,所述曲前列素衍生物为曲前列素的酸衍生物、前药、多晶型或者异构体。
根据本发明,所述PDE4抑制剂可具体地选自Ro20-1724、异丁司特、罗氟司特及其N-氧化物、西洛司特、BAY19-8004、CC3、AWD12-281、SCH351591、西拉米特(Ciclamilast)、吡拉米司特、CGH2466、松叶菊碱、咯利普兰、四羟黄酮和屈他维林。
根据本发明,所述PDE5抑制剂可具体地选自阿伐那非(Avanafil)、Lodenafil、米罗那非、枸橼酸西地那非、他达那非、伐地那非和优地那非;所述PDE7和PDE8抑制剂可选自双嘧达莫、BRL-50481和PF-04957325。
根据本发明的具体实施方案,所述组合物具体地由一种类型的前列环素类似物和一种类型的PDE4抑制剂构成。
作为具体的实施方案,所述组合物包含曲前列素和选自RO20-1724、罗氟司特和异丁司特的PDE4抑制剂。
在本发明另外的实施方案中,所述组合物包含选自PDE5、PDE7或者PDE8抑制剂的另外的PDE抑制剂。
在另外的实施方案中,本发明提供不含有干扰素的组合物。
具体地,将本发明的组合物配制为药物组合物。
任何已知的给药形式可用于给予本发明的组合,例如其可为静脉内或者皮下给药或者吸入给药,或者为选自持续释放形式、片剂和胶囊剂的口服可用形式。
根据具体的实施方案,曲前列素或者其药用盐的有效量优选为约1.0ng/kg体重,异丁司特优选至多为5x30mg,优选至多为2x30mg,PDE4抑制剂的有效量为约0.5mg。此外,可含有约每个抑制剂0.5mg的有效量的PDE5和PDE7抑制剂组中的一种或者多种抑制剂。
本发明还提供了用于增加细胞中cAMP水平的体外方法,其中使得所述细胞与至少一种前列环素或者前列环素类似物以及至少一种PDE4抑制剂或者其药用盐接触。此外,PDE5、PDE7和/或者PDE8抑制剂可进一步用于所述方法中。
具体地,所述细胞为上皮细胞,更具体地其可为支气管上皮细胞。
本发明还提供了治疗组合,其包含至少一种前列环素或者前列环素类似物以及至少一种PDE4抑制剂或者其药用盐,其中所述前列环素类似物和PDE4抑制剂以一起足以治疗和/或者预防至少一种与囊性纤维化相关的症状的量来提供。更具体地,配制所述前列环素类似物和PDE4抑制剂以用于吸入给药。
根据可选择的实施方案,所述治疗组合物含有至少一种另外的选自PDE5、PDE7和PDE8抑制剂的抑制剂。
附图说明
图1:在与单独的曲前列素或者曲前列素与PDE4抑制剂异丁司特(100μM)和西洛他唑(100μM)的组合孵育后,cAMP在IB3-1细胞中的累积。
图2:在与曲前列素与PDE4抑制剂RO-20-1724(100μM)和罗氟司特(10μM)的组合孵育后,cAMP在IB3-1细胞中的累积
图3:在短暂表达CFTR-wt的人支气管上皮IB3-1细胞系中Cl-流被曲前列素的激活。
图4:在不存在以及存在指定浓度的双嘧达莫、异丁司特、RO20-1724或者罗氟司特的情况下,由10μM曲前列素刺激的cAMP在IB3-1细胞中的累积。将细胞用[3H]腺嘌呤进行代谢性预先标记4小时,且随后与指定化合物孵育30分钟。[3H]cAMP的形成如在材料和方法中所阐述的来确定。数据为平均值±标准差(n=3)。
图5:针对曲前列素-诱导的cAMP在IB3-1细胞中的累积的浓度响应曲线。将细胞与增加浓度的曲前列素在不存在以及存在指定浓度的异丁司特、RO20-1724或者罗氟司特的情况下孵育。将细胞用[3H]腺嘌呤进行代谢性预先标记4小时,且随后与指定化合物孵育30分钟。[3H]cAMP的形成如在材料和方法中所阐述的来确定。数据为平均值±标准差(n=3)。
图6:所选的磷酸二酯酶抑制剂对cAMP在IB3-1细胞中的基线累积的作用。将细胞用[3H]腺嘌呤进行代谢性预先标记4小时,且随后在不存在(基线)以及存在指定浓度的双嘧达莫、Ro-20-1724或者罗氟司特的情况下孵育30分钟。[3H]cAMP的水平如在材料和方法中所阐述的来确定。数据为平均值±标准差(n=3)。
具体实施方式
发明人已经惊奇地发现前列环素或者类似物或者其药用盐与PDE4抑制剂的组合可用于治疗囊性纤维化。其显示了相比于单一物质的使用,前列环素或者前列环素类似物和PDE4抑制剂的组合具有对cAMP增加的协同作用,特别是对在侵袭的人气道上皮细胞中的cAMP增加的协同作用。所述作用可进一步由于另外的选自PDE5、PDE7和PDE8抑制剂的PDE抑制剂的存在而增强。
合成的前列环素类似物可为例如但不限于曲前列素、伊洛前列素、西卡前列素或者贝前列素。
曲前列素的市售名称为RemodulinTM。曲前列素为(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-六氢-2-羟基-1-[(3S)-3-羟基辛基]-1H-苯并[f]茚-5-基]氧基]乙酸一钠盐。
伊洛前列素的市售名称为“Ilomedine”且为5-{(E)-(1S,5S,6R,7R)-7-羟基-6[(E)-(3S,4RS)-3-羟基-4-甲基-1-辛-6-烯基]-二环[3.3.0]辛-3-亚基}戊酸。
贝前列素为2,3,3a,8b-四氢-2-羟基-1-(3-羟基-4-甲基-1-辛-6-炔基)-1H-环戊二烯并(b)苯并呋喃-5-丁酸。
西卡前列素为2-[(2E)-2-[(3aS,4S,5R,6aS)-5-羟基-4-[(3S,4S)-3-羟基-4-甲基壬-1,6-二炔基]-3,3a,4,5,6,6a-六氢-1H-戊烯-2-亚基]乙氧基]乙酸。
关于本发明的前列环素、PDE4和PDE5、PDE7或者PDE8抑制剂,术语“前列环素类似物”、“抑制剂类似物”或者“PDE4、PDE5、PDE7或者PDE8抑制剂类似物”是指所述物质的衍生物或者类似物。术语"类似物"或者"衍生物"涉及在结构和功能上类似于另外的化学物质(通常在结构上存在单一元素或者基团的不同)的化学分子,其可通过修饰多于一个基团(例如2、3或者4个基团)而变得不同,只要其仍保留与母体化学物质相同的功能。所述修饰对于本领域技术人员而言是常规方法,且包括例如额外的或者取代的化学部分,诸如酸的酯或者酰胺,保护基团诸如对于醇或者硫醇的苄基以及对于胺的叔丁氧基羰基。也包括对于烷基侧链的修饰诸如烷基取代(例如甲基、二甲基、乙基等)、修饰达到侧链的饱和或者不饱和水平以及添加经修饰的基团诸如取代的苯基和苯氧基。衍生物也可包括缀合物诸如生物素或者抗生物素蛋白部分、酶诸如辣根过氧化物酶等以及放射标记的生物发光、化学发光或者荧光部分。此外,可将所述部分加入至本申请所述的试剂中以改变它们的药代动力学性质,诸如增加体内或者离体半衰期或者增加它们的细胞渗透性质等其它预期性质。也包括前药,其已知为增强药物制剂的众多预期性质(例如溶解性、生物利用度、制造等)。术语"衍生物"在其范围内也包括已经对母体序列进行的变更,包括添加、删除和/或者取代,以提供功能相当或者功能改善的分子。
适当的前列环素或者前列环素类似物衍生物包括但不限于曲前列素、伊洛前列素、西卡前列素或者贝前列素的酸衍生物、前药、持续释放形式、吸入形式和口服形式。
根据本发明的具体实施方案,所述曲前列素衍生物选自曲前列素的酸衍生物、前药、多晶型或者异构体。
类似地,伊洛前列素、西卡前列素或者贝前列素衍生物可为其酸衍生物、前药、多晶型或者异构体。术语前列环素衍生物也涵盖其药用盐。本发明的前列环素或者前列环素类似物的药用盐可在化合物的酸性和碱性基团(诸如氨基官能团)之间形成,或者在碱和化合物的酸性基团(诸如羧基官能团)之间形成。
具体地,前列环素类似物的生理学可接受盐包括衍生自碱的盐。碱盐包括铵盐(诸如季铵盐)、碱金属盐诸如钠盐和钾盐、碱土金属盐诸如钙盐和镁盐、与有机碱(诸如二环己基胺和N-甲基-D-葡萄糖胺)的盐以及与氨基酸(诸如精氨酸和赖氨酸)的盐。
具体地,曲前列素的使用在本发明中是有优势的。曲前列素可成功地增强囊性纤维化患者的肺上皮细胞中的ΔF508CFTR表达和/或者氯通道功能。
已经令人惊奇地显示前列环素类似物与PDE4抑制剂的组合且任选地与PDE5和/或者PDE7和/或者PDE8抑制剂的组合导致cAMP产生的协同性刺激和/或者支气管上皮细胞中的cAMP含量增加。
有趣的是,PDE3抑制剂如阿那格雷和西洛他唑在试验中不能诱导任何的cAMP累积。
考虑到这种通过IP受体刺激cAMP产生的能力和IP受体仅存在于少数细胞类型(比如肺上皮细胞),前列环素或其类似物(例如曲前列素)可能能够以特异的方式诱导CFTR和mutCFTR的表达和门控,可以用于治疗CF,特别是当与所述PDE4抑制剂组合时可诱导气道上皮内的cAMP水平的长时间持续的增加。
根据另外的实施方案,所述cAMP增加可进一步被PDE4抑制剂选自PDE5、PDE7和/或者PDE8抑制剂的PDE抑制剂的另外的组合所诱导。
PDE4抑制剂被证实用于治疗COPD和哮喘;COPD和哮喘中的主要靶标是降低沿气道的平滑肌细胞的高反应性。很早就已知提升平滑肌细胞中的cAMP水平能够经肌球蛋白轻链激酶的作用引起平滑肌舒张。此外,认为PDE4抑制剂降低免疫应答,其通过靶向单核细胞、嗜曙红细胞和嗜碱性粒细胞、B和T细胞例如炎症细胞来驱使变应性哮喘。这两种机制均不与囊性纤维化中的作用模式相关。在囊性纤维化中,cAMP水平需要在非常不同的细胞腔隙(即气道上皮)中提升。事实上,据本申请人所知,没有科学报告显示了PDE4是在气道上皮内增强受体介导的cAMP累积的有关的同工型。
根据本发明,可使用具有对PDE4酶的抑制活性的任何PDE4抑制剂或者其类似物。因此,不排除所述PDE4抑制剂也可进一步抑制其它PDE酶。
具体地,所述PDE4抑制剂可为特异性PDE4抑制剂。
本发明的PDE4抑制剂可为但不限于Ro20-1724、异丁司特、罗氟司特(3-(环丙基甲氧基)-N-(3,5-二氯吡啶-4-基)-4-(二氟甲氧基)苯甲酰胺)及其N-氧化物、西洛司特、BAY19-8004、CC3、AWD12-281(N-(3,5-二氯-4-吡啶基)-2-[1-(4-氟苄基)-5-羟基-1H-吲哚-3-基]-2-氧代乙酰胺)、SCH351591(N-(3,5-二氯-1-氧化-4-吡啶基)-8-甲氧基-2-(三氟甲基)-5-喹啉甲酰胺)、西拉米特、吡拉米司特、CGH2466、松叶菊碱、咯利普兰、四羟黄酮和屈他维林或者它们的功能类似物。
更具体地,用于预防或者治疗CF(具体地通过提升患有CF个体的支气管上皮细胞中的cAMP水平)的组合物可具体地包含曲前列素和罗氟司特,或者曲前列素和异丁司特,或者曲前列素和Ro-20-1724。PDE5抑制剂已经显示了增加平滑肌细胞中的环状核苷酸第二信使水平。
根据本发明,可使用具有对PDE5酶的抑制活性的任何PDE5抑制剂或者其类似物。因此,不排除所述PDE5抑制剂也可进一步抑制其它PDE酶。
根据本发明,所述PDE5抑制剂可具体地选自阿伐那非(4-[(3-氯-4-甲氧基苄基)氨基]-2-[2-(羟基甲基)-1-吡咯烷基]-N-(2-嘧啶基甲基)-5-嘧啶甲酰胺)、Lodenafil(二-(2-{4-[4-乙氧基-3-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)-苯磺酰基]哌嗪-1-基}-乙基)碳酸酯)、米罗那非(5-乙基-3,5-二氢-2-[5-([4-(2-羟基乙基)-1-哌嗪基]磺酰基)-2-丙氧基苯基]-7-丙基-4H-吡咯并[3,2-d]嘧啶-4-酮)、枸橼酸西地那非(1-[4-乙氧基-3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)苯基磺酰基]-4-甲基哌嗪)、他达那非(6R-反式)-6-(1,3-苯并二氧杂环戊烯-5-基)-2,3,6,7,12,12a-六氢-2-甲基-吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮)、伐地那非(4-[2-乙氧基-5-(4-乙基哌嗪-1-基)磺酰基-苯基]-9-甲基-7-丙基-3,5,6,8-四氮杂二环[4.3.0]壬-3,7,9-三烯-2-酮)或者优地那非(3-(1-甲基-7-氧代-3-丙基-4,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)-N-[2-(1-甲基吡咯烷-2-基)乙基]-4-丙氧基苯磺酰胺)或者它们的任何功能类似物。
在本发明的具体实施方案,所述组合物可包含曲前列素、罗氟司特和任选地PDE5、PDE7或者PDE8抑制剂,或者曲前列素、异丁司特和任选地PDE5、PDE7或者PDE8抑制剂,或者曲前列素、Ro-20-1724和任选地PDE5、PDE7或者PDE8抑制剂。
在本发明另外的实施方案中,所述组合物可包含贝前列素、罗氟司特和任选地PDE5、PDE7或者PDE8抑制剂,或者贝前列素、异丁司特和任选地PDE5、PDE7或者PDE8抑制剂,或者贝前列素、Ro-20-1724和任选地PDE5、PDE7或者PDE8抑制剂。
在本发明另外的实施方案中,所述组合物可包含伊洛前列素、罗氟司特和任选地PDE5、PDE7或者PDE8抑制剂,或者伊洛前列素、异丁司特和任选地PDE5、PDE7或者PDE8抑制剂,或者伊洛前列素、Ro-20-1724和任选地PDE5、PDE7或者PDE8抑制剂。
在本发明另外的实施方案中,所述组合物可包含西卡前列素、罗氟司特和任选地PDE5、PDE7或者PDE8抑制剂,或者西卡前列素、异丁司特和任选地PDE5、PDE7或者PDE8抑制剂,或者西卡前列素、Ro-20-1724和任选地PDE5、PDE7或者PDE8抑制剂。
根据本发明,可使用具有对PDE7或者PDE8酶的抑制活性的任何PDE7或者PDE8抑制剂或者其类似物。因此,不排除所述PDE7或者PDE8抑制剂也可进一步抑制其它PDE酶。
根据本发明,所述PDE7抑制剂可具体地选自双嘧达莫和BRL50481。
根据本发明,所述PDE8抑制剂可具体地选自1,5-取代的哌啶甲酰胺和PF-4957325。
在本发明的可选择的实施方案中,所述组合物可具体地包含曲前列素、罗氟司特和双嘧达莫,或者曲前列素、异丁司特和双嘧达莫,或者曲前列素、Ro-20-1724和双嘧达莫。
在本发明的另外的可选择的实施方案中,所述组合物可具体地包含贝前列素、罗氟司特和双嘧达莫,或者贝前列素、异丁司特和双嘧达莫,或者贝前列素、Ro-20-1724和双嘧达莫。
在本发明的另外的可选择的实施方案中,所述组合物可具体地包含伊洛前列素、罗氟司特和双嘧达莫,或者伊洛前列素、异丁司特和双嘧达莫,或者伊洛前列素、Ro-20-1724和双嘧达莫。
在本发明的另外的实施方案中,所述组合物可具体地包含西卡前列素、罗氟司特和双嘧达莫,或者西卡前列素、异丁司特和双嘧达莫,或者西卡前列素、Ro-20-1724和双嘧达莫。
可选择地,所述组合物可包含曲前列素、罗氟司特和BRL50481,或者曲前列素、异丁司特和BRL50481,或者曲前列素、Ro-20-1724和BRL50481。
可选择地,所述组合物可具体地包含曲前列素、罗氟司特和PF-4957325,或者曲前列素、异丁司特和PF-4957325,或者曲前列素、Ro-20-1724和PF-4957325。
根据本发明,术语“至少一种”或者“一个”是指存在一种类型的前列环素或者前列环素类似物以及一种类型的PDE4抑制剂和任选地一种或者多种PDE5、PDE7或者PDE8抑制剂以用于治疗或者预防囊性纤维化,特别是用于增加支气管上皮细胞中的cAMP水平。然而,可选择地,所述组合物也可包含多于一种类型的前列环素或者前列环素类似物以及多于一种类型的PDE4抑制剂和任选地一种或者多种PDE5、PDE7或者PDE8抑制剂(特别是两种、三种、四种或者多于四种类型),或者前列环素或者前列环素类似物以及PDE4和任选地PDE5、PDE7和/或者PDE8抑制剂的任何组合。
本发明进一步提供了具体组合物,其包含曲前列素以及一种或者多种选自RO20-1724、罗氟司特和异丁司特的PDE4抑制剂。
本发明组合物可配制为药物组合物。
本发明的组合物可以用于给药的任何形式存在。
根据本发明所给予的为了获得治疗或者预防效果的化合物的具体剂量当然将由围绕该情况的具体条件来确定,包括例如给药途径、个体患者的年龄、体重和反应、待治疗的病症以及患者症状的严重性。
一般而言,本发明的化合物最预期地以通过将获得有效结果而不引起任何严重副作用的浓度来给予,且可作为单一单位剂量来给予,或者如果需要,可将所述剂量分为在一天当中的适当时间给予的便利的亚单位。
所述组合物可以各种全身性和局部制剂来提供。本发明的全身性或者局部制剂选自口服、颊内、肺内、直肠、子宫内、皮内、局部、真皮、肠胃外、瘤内、颅内、肺内、含服、舌下、鼻部、皮下、血管内、鞘内、吸入、吸收、关节内、腔内、移植、经皮、离子电渗疗法、眼内、眼部、阴道、视觉、静脉内、肌内、腺内、器官内、淋巴管内、缓释和肠溶包衣制剂。这些不同制剂的实际配制和配方在本领域中是已知的且不需要在此详述。所述组合物可一天给予一次或者若干次。
适于呼吸、鼻内、肺内和吸入给药的制剂是优选的,如局部、口服和肠胃外制剂。一般而言,所述制剂通过如下制备:使得活性化合物与液体载体、精细分散的固体载体或者两者均匀且充分地缔合,然后如果需要,将产物成型为预期制剂。
适于口服给药的组合物可以离散的单元存在,诸如胶囊剂、扁囊剂、锭剂或者片剂,其各自含有组合物,其作为粉末或者颗粒;作为含水或者不含水液体中的溶液剂或者混悬剂;或者作为水包油或者油包水乳剂。
适于肠胃外给药的组合物包括活性化合物的无菌含水和不含水注射溶液,该制剂优选与接受者的血液等渗。这些制剂可含有抗氧化剂、缓冲剂、抑菌剂和使得所述组合物与接受者的血液等渗的溶质。含水和不含水无菌混悬液可包含助悬剂和增稠剂。所述组合物可存在于单位剂量或者多剂量容器中,例如密封的安瓿和小瓶,且可储存在冷冻干燥或者低压冻干的条件下,这仅需要在使用前立即加入无菌液体载体例如盐水或者注射用水。
鼻部和滴注制剂包含活性化合物与防腐剂和等渗剂的纯净水溶液。将所述制剂优选调节为与鼻粘膜相匹配的pH和等渗状态。
本发明公开的组合物可通过任何适当方法由受试者的吸入、呼吸、鼻部给药或者肺内滴注(入肺)而给予至呼吸系统,且任选通过产生包含粉末或者液体的鼻部、肺内、适于呼吸或者吸入的颗粒的气雾剂或者喷雾剂来给药。包含活性化合物的适于呼吸或者吸入颗粒可由受试者例如通过吸入或者鼻部给药或者滴注至呼吸道或者肺本身来吸入。所述制剂可包含本发明的活性化合物的适于呼吸或者吸入液体或者固体颗粒,包括具有足够小以在吸入后经过口和喉并且继续进入支气管和肺气泡的粒度的适于呼吸或者吸入颗粒。一般而言,颗粒直径的范围为约0.05、约0.1、约0.5、约1、约2至约4、约6、约8、约10微米。更具体地,约0.5至小于约5μm的直径为可呼吸或者吸入的。包含在气雾剂或者喷雾剂中的不可吸入大小的颗粒趋于在咽喉中沉积并被吞咽。因此,气雾剂中的不可吸入颗粒的量被最小化。对于鼻部给药或者肺内滴注,粒度的直径范围优选为约8、约10、约20、约25至约35、约50、约100、约150、约250、约500μm,以保证滞留在鼻腔内或者用于滴注且直接沉积于肺中。可将液体制剂喷射至呼吸道或者鼻部以及肺中,特别是当给予至新生儿和婴儿时。
包含活性化合物的液体颗粒的气雾剂可由任何适当的装置诸如喷雾器来产生。喷雾器为可商购得到装置,其将活性成分的溶液或者混悬液通过压缩气体(通常为空气或者氧气)的加速装置转化为治疗性气雾。用于该喷雾器的适当组合物由液体载体中的活性成分构成,所述活性成分占组合物至多40%w/w,但优选小于20%w/w的载体通常为水或者稀的含水醇溶液,其优选通过加入例如氯化钠被制成与体液等渗。如果所述组合物并未被制成无菌的,则任选的添加剂包括防腐剂例如羟基苯甲酸甲酯、抗氧化剂、矫味剂、挥发油、缓冲剂和表面活性剂。包含活性化合物的固体颗粒的气雾剂也可用任何市售的颗粒药物气雾发生器来产生。用于给予固体颗粒药物(即如上解释的可吸入的产物颗粒)的气雾发生器以适于人给药的速率产生一定体积的含有预定计量的药物的气雾剂。所述气雾发生器的实例包括计量吸入器和充气器。
在一个实施方案中,所述递送装置包括递送单一剂量或者多个剂量的组合物的干粉吸入器(DPI)。所述单一剂量吸入器可作为一次性试剂盒来提供,其无菌地预先加载有足以用于一次施用的制剂。所述吸入器可作为加压吸入器来提供,且所述制剂在可刺透或者可打开的胶囊或者药盒中。所述试剂盒也可任选地包含在分开的容器中的试剂诸如其它治疗化合物、赋形剂、表面活性剂(意在作为治疗剂以及制剂成分)、抗氧化剂、矫味剂和着色剂、填充剂、挥发油、缓冲剂、分散剂、表面活性剂、抗氧化剂、矫味剂、填充剂、推进剂和防腐剂等其它用于不同制剂的适当添加剂。
由于某些前列环素类似物如曲前列素的高代谢稳定性,或者如果作为前列环素或者前列环素类似物的基于液体的或者Peg化形式来提供,所述物质也可作为储库(depot)药物来给予。
PDE4、PDE5、PDE7和PDE8抑制剂也为代谢稳定的,因此前列环素或者前列环素类似物以及PDE4抑制剂的组合也可任选地与一种或者多种PDE5、PDE7或者PDE8抑制剂一起配制为储库药物。
组合物的气雾化递送可导致试剂在肺内的更均匀的分布,由此获得深入的肺部递送。因此,由于所述试剂在肺的作用位点的持续存在,可降低施用的剂量。
所述组合物可例如通过喷雾器来给予。喷雾器递送方法的优势为较少的物质达到体循环。所述组合物可一天给予若干次,例如一天5-10次,然而由于前列环素或者前列环素类似物和PDE4任选地与一种或者多种PDE5、PDE7和/或者PDE8抑制剂的组合的协同作用,通常可降低所述给药频率。
组合物可以与本领域已知的任何药用物质或载体或赋形剂一起给予。这些可以是例如,但不限于水、诸如NaOH和KOH的中和剂、稳定剂、DMSO、盐水、内铵盐(betaine)、牛磺酸等。
名词“药用”意味着被联邦或州政府的管理机构批准或者在美国上市的。
名词“载体”是指与药物组合物一同给予的稀释剂、辅料、赋形剂或媒介物。盐水溶液和水性右旋糖和甘油溶液也可以作为液态载体,特别是作为注射液的载体。合适的赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等等。合适的药物载体的例子在"Remington's Pharmaceutical Sciences"by E.W.Martin中描述。制剂应当根据给药模式来选择。
本发明组合物的量可由本领域任何技术人员来选择,具体是前列环素或者前列环素类似物或者其药用盐的量,具体地曲前列素的量为至少1.0ng/kg体重。PDE4或者PDE5抑制剂的量也可由本领域技术人员容易地选择。具体地,PDE4或者PDE5或者PDE7或者PDE8抑制剂的量为约0.5mg(罗氟司特)或者约30mg(异丁司特),每天至少给予一次,具体地每天至少给予两次。
本发明还提供了增加细胞中cAMP水平的方法,其中使得所述细胞与至少一种前列环素或者前列环素类似物以及至少一种PDE4和任选地至少一种PDE5、PD7或者PDE8抑制剂接触。相比于使用前列环素或者PDE4和/或者PDE5或者PDE7或者PDE8抑制剂的单一治疗,cAMP在所述细胞中的增加可为至少10%,优选至少25%,优选至少50%,更优选至少100%。
本发明还提供了治疗组合,其包含至少一种前列环素类似物以及至少一种PDE4和任选地至少一种PDE5和/或者PDE7抑制剂和/或者PDE8抑制剂,其中所述前列环素类似物和PDE4和/或者PDE5抑制剂和/或者PDE7抑制剂和/或者PDE8抑制剂以一起足以治疗和/或者预防至少一种与囊性纤维化相关的症状的量来提供。具体地,可通过给予本发明的治疗组合制剂来实现CF患者的肺上皮细胞中的cAMP水平的增加。具体地,将至少一种前列环素类似物以及PDE4和任选地一种或者多种PDE5、PDE7或者PDE8抑制剂配制为用于吸入给药。
在本发明具体的实施方案中,公开了用于治疗囊性纤维化的组合疗法。根据具体的实施方案,与CF患者的支气管上皮细胞中的cAMP水平降低相关的症状可通过使用本发明的组合疗法来治疗或者预防。可能地,也可给予一种或者多种额外的试剂。
所述前列环素或者前列环素类似物以及PDE4和任选地PDE5、PDE7或者PDE8抑制剂可在例如单一片剂或者胶囊剂或者吸入制剂中一起给予,或者本发明的所述PDE4以及任选地其它PDE抑制剂以及任选额外的试剂可与前列环素或者前列环素类似物分开给予。
本发明进一步提供了试剂盒及其在治疗或者预防与受试者囊性纤维化相关的病症中的用途,所述试剂盒包含(i)有效量的前列环素或者前列环素类似物,(ii)PDE4抑制剂,具体为罗氟司特、Ro-20-1724或者异丁司特,以及任选地一种或者多种选自PDE5、PDE7和PDE8抑制剂的化合物,(iii)一种或者多种药用载体和/或者添加剂,以及(iv)针对治疗或者预防受试者优选人类的囊性纤维化的使用说明。
所述组分(i)、(ii)和(iii)可为适于静脉内给予、吸入或者口服给予的形式。
本申请描述的实施例用于对本发明进行阐述,但不是对发明的限制。根据本发明描述了本发明的不同实施方案。在不脱离本发明精神和范围的情况下,可以对本申请描述和示例说明的技术进行多种改动和变化。因此,应当理解实施例仅用于阐述,而不是对发明范围的限制。
实施例
实施例1:
将IB3-1细胞接种到6孔板(图1中0.2*106个细胞/孔;图2中0.4*106个细胞/孔)中的完全生长培养基(LHC-8+5%FCS)中。第二天,通过用含有腺苷脱氨酶(1单位/ml)的Dulbecco改进的Eagle培养基(Dulbecco’s ModifiedEagle’s Medium,DMEM)中的[3H]腺嘌呤(1μCi/孔)孵育4小时,对腺嘌呤核苷酸库进行代谢标记。此后,将培养基用新鲜培养基替换;通过单独加入曲前列素(范围为0.1至30μM的对数性间隔浓度)或者曲前列素与指定浓度的PDE-抑制剂的组合来刺激细胞。孵育30分钟后,通过加入高氯酸将细胞裂解。
[3H]cAMP的形成通过在Dowex50WX-4和中性氧化铝柱子上进行顺序色谱法、然后对洗脱液进行液体闪烁计数来确定。测定一式三份进行。
结果示于图1和2中。图1和图2的最大响应之间的差异主要是由于以下事实:图2中的每孔细胞个数约为图1中所采用的细胞个数的两倍。
实施例2:
IB3-1细胞内源表达突变的CFTR-ΔF508,该蛋白保留在细胞内。利用合适的操作(例如药物分子伴侣或低温孵育),有可能将突变体CFTR-ΔF508从内质网转运到ER;当插入到细胞表面时,通过提高cAMP可以刺激Cl-电导。但是得到的Cl-电导很小。为了清楚地证明曲前列素诱导的cAMP累积转化为CFTR的活化,发明人瞬时表达了GFP标记的野生型CFTR(GFP标签使得能够识别在细胞表面表达该蛋白的细胞)。由图3可以看出,曲前列素导致从-40mV保持电位到+60mV的去极化引起电流强劲激活。最大效应被延迟,即仅在充盈(wash-in)化合物后的数秒内观察到。类似地,在关闭(turn-off)反应中也有滞后;只在廓清(washout)后约100秒时电流才衰减到基础水平。这些延迟的反应反映了(i)介入性的信号级联放大(即GS的受体依赖性激活、cAMP形成的GαS依赖性激活和接着发生的CFTR的蛋白激酶A依赖性磷酸化)和(ii)磷酸二酯酶对增加的cAMP的去活化被延迟。如果细胞用福斯高林(腺苷酰环化酶的直接激活剂,作为阳性对照)刺激,可以看到类似的延迟现象。
这些观察结果证明,曲前列素可以活化支气管上皮细胞中的CFTR。
方法:
电生理学
全细胞膜片钳技术用于在22±1.5℃用Axoclamp200B膜片钳放大器(Axon Instruments)进行电流记录。当充入记录电极液(组成:110mM CsCl,5mM EGTA,2mM MgCl2,1mM K2.ATP,10mM Hepes,pH用CsOH调节至7.2)时,电极的电阻在1和2MΩ之间。电压钳试验方案和数据获取用pclamp6.0软件(Axon Instruments)进行。数据在2kHz(-3dB)进行低通滤过,在10-20kHz数字化。细胞持续用外部溶液(组成:145mM NaCl,4.5mM KCl,2mMCaCl2,1mM MgCl2,5mM葡萄糖,10mM Hepes,pH用NaOH调节至7.4)灌注。指明的情况中,外部溶液含有曲前列素(10μM)或福斯高林(5μM),通过电控压力阀实现溶液间的转换。
基于实施例1的结果,预期有持续的响应,条件是曲前列素与PDE4或者5抑制剂例如10μM罗氟司特或者100μM异丁司特或者10-100μM他达那非或者昔多芬或者伐地那非组合。
细胞培养:
I3B-1细胞生长在培养皿(Nunc,3.5cm直径)上,所述培养皿涂覆含有5%胎牛血清(FCS)的LHC-8培养基(Gibco)中的纤连蛋白(10μg/mL)大鼠胶原蛋白I(30μg/mL)和BSA10μg/mL)。按照制造商的说明,通过使用Lipofectamine(Invitrogen),用促进GFP标记的的人野生型CFTR表达的质粒短暂转染细胞。
记录+60mV时的全细胞膜片钳中的代表性的电流幅度。在荧光下挑选表达GFP标记的野生型CFTR的瞬时转染IB3-1细胞,夹在-40mV的保持电位下。将电压阶跃到+60mV并保持50ms诱导去极化,记录电流幅度。曲前列素(10μM终浓度,TP)充盈始于时间点50s,止于125s。福斯高林在275s充盈,在375s去除。结果如图3所示。
实施例3
简介
前面的观察表明,在人气道上皮细胞中,曲前列素-诱导的cAMP累积由磷酸二酯酶-4(PDE4)同工型的抑制剂特异性增强。
材料和方法
细胞系和细胞培养:
下述人支气管上皮细胞系经ATCC获得:
BEAS-2B(ATCC CRL-9609)、NuLi-1(ATCC CRL-4011)、IB3-1(ATCCCRL-2777)、CuFi-1(ATCC CRL-4013)
使用在ATCC推荐方法中阐述的培养条件来培养细胞,例如使得IB3-1细胞在37℃在5%CO2潮湿气氛中生长在培养皿上,所述培养皿使用含有5%胎牛血清(FCS)的LHC-8培养基(Gibco)中的纤连蛋白(10μg/mL)大鼠胶原蛋白I(30μg/mL)和BSA10μg/mL)涂覆。使得BEAS-2B细胞在37℃在5%CO2潮湿气氛中生长在培养皿上,所述培养皿使用BEGM培养基(Lonza)中的胶原IV(60μg/ml在0.25%乙酸)预先涂覆;BEGM试剂盒所提供的GA-1000(庆大霉素-两性霉素B混合物)并未加入至培养基中。CFTR的内源性表达水平过低以至于不能获得可靠信号。因此,按照制造商的说明,通过采用Lipofectamine(Invitrogen),用促进GFP标记的人野生型CFTR表达的质粒瞬时转染BEAS-2B细胞。表达该GFP标记的CFTR的细胞通过荧光显微法来鉴定并进行如下阐述的膜片箝记录。
cAMP累积测定:
将IB3-1细胞在完全生长培养基(LHC-8+5%FCS)中接种于6-孔板的PDL-涂覆的孔(2-2.5*105个细胞/孔)中。第二天,将细胞腺嘌呤核苷酸库通过与在腺苷脱氨酶(5μg/ml)的存在下在Dulbecco改进的Eagle培养基(DMEM)中的[3H]腺嘌呤(1μCi/孔)孵育4小时来进行代谢标记。随后,将培养基用新鲜DMEM替换并通过在37℃历时20分钟在不存在以及存在不同浓度的以下磷酸二酯酶(PDE)抑制剂的情况下加入5μM福斯高林(腺苷酸环化酶的直接活化剂)或者10μM曲前列素来刺激cAMP的形成:异丁司特(0.3-1000μM)、Ro-20-1724(0.03-300μM)、罗氟司特(1nM-10μM)、双嘧达莫(0.01-100μM)、氨力农(1、10、100μM)、阿那格雷(1、10、100μM)、依诺昔酮(1、10、100μM)、米力农(1、10、100μM)和西洛他唑(0.1-100μM)。在某些情况下,这些抑制剂对于基线cAMP累积的作用通过在不存在任何另外的刺激物的情况下将细胞与增加浓度的PDE-抑制剂(即双嘧达莫、异丁司特和Ro-20-1724,1、10和100μM;罗氟司特,0.1、1和10μM)孵育来检测。通过加入单独的曲前列素(0.1-30μM)或者曲前列素与100μMRo-20-1724、100μM异丁司特或者5μM罗氟司特的组合来获得曲前列素的浓度响应曲线。通过加入2.5%高氯酸以及0.1mM(未标记的)cAMP来终止一式三份进行的反应。通过在Dowex50W-X4和中性氧化铝柱上进行的顺序色谱法来分离[3H]cAMP。[3H]cAMP的形成通过液体闪烁计数来定量。
电生理学-膜片箝记录:
全细胞膜片箝技术用于在22±1.5℃使用Axoclamp200B膜片箝放大器(Axon Instruments)进行的电流记录。当充入记录电极液(组成:110mM CsCl,5mM EGTA,2mM MgCl2,1mM K2.ATP,10mM Hepes,pH用CsOH调节至7.2)时,电极的电阻在1和2MΩ之间。电压钳试验方案和数据获取用pclamp6.0软件(Axon Instruments)进行。数据在2kHz(-3dB)进行低通滤过,在10-20kHz数字化。细胞持续用外部溶液(组成:145mM NaCl,4.5mM KCl,2mMCaCl2,1mM MgCl2,5mM葡萄糖,10mM Hepes,pH用NaOH调节至7.4)灌注。指明的情况中,外部溶液含有曲前列素(10μM)或福斯高林(5μM),通过电控压力阀实现溶液间的转换。
在不存在以及存在磷酸二酯酶抑制剂的情况下cAMP在IB3-1细胞系中的累积:
对PDE-同工型的检测可预测出PDE-抑制剂应当具有对于在人支气管上皮细胞中的cAMP累积的显著效应。此外,该分析提供了存在磷酸二酯酶的额外同工型的证据。因此,测试了PDE-4选择性抑制剂罗氟司特和异丁司特并将它们的作用与如下所述的若干额外的PDE-抑制剂进行比较:RO20-1724,一种非选择性PDE-抑制剂,优选为PDE4-抑制剂;双嘧达莫,其阻断平衡型核苷转运体-1和-2(ENT1-和ENT2),以及抑制PDE5、PDE7A、PDE8A、PDE10A和PDE11(Soderling et al.,1998;Hetman et al.,2000a&b;Omori&Kotera,2007);氨力农、米力农和西洛他唑,其为PDE3-同工型的选择性抑制剂;阿那格雷,其抑制PDE2和PDE3。异丁司特相比于罗氟司特而言具有较弱的选择性且也抑制PDE10-和PDE11-同工型。该方法的重点在于调节cAMP-水平;因此所述cGMP-特异性酶PDE5、PDE6和PDE9并未被进一步考虑(Bender&Beavo,2006;Omori&Kotera,2007)。
细胞通常表达腺苷酸环化酶的许多同工型。在许多情况下,与Gs偶联的受体不能够进入腺苷酸环化酶的整个细胞库。相反,福斯高林刺激腺苷酸环化酶的所有同工型。在不存在磷酸二酯酶抑制的情况下,将cAMP快速水解以使得其仅在稳态累积达到低水平。磷酸二酯酶的抑制导致cAMP的累积。罗氟司特、异丁司特、双嘧达莫和RO20-1724本质上增强了由5μM福斯高林引发的cAMP累积。罗氟司特为最有效的抑制剂且双嘧达莫为具有相对较弱有效性的抑制剂。异丁司特和RO20-1724相比于罗氟司特更加有效。这些数据一起表明PDE4-同工型促进很大程度的cAMP的水解。如果cAMP累积由曲前列素引发,则对于所有抑制剂的浓度响应曲线位移至左侧。该向左位移表明经受体刺激产生的cAMP能够更加容易地由磷酸二酯酶降解。一种可能的解释是磷酸二酯酶在受体附近的锚定(Francis et al.,2011)。双嘧达莫的较高的效能也表明PDE8或者PDE10的可能的作用。磷酸二酯酶抑制剂的主要作用是增强cAMP累积:尽管Emax(即最大效应增加)位移,但是激动剂的表观亲和力(即其EC50)并未位移。
在不存在外源性加入的激动剂(或者不存在福斯高林)的情况下,所述PDE-抑制剂本身不引起cAMP累积的任何可估计的增加。这是可预期的;腺苷酸环化酶的基线活性是极低的且其需要经Gs的受体依赖性活化的输入以催化cAMP的形成。然而,在细胞培养条件下-即限定的培养基,不存在任何激动剂。
PDE-抑制增强了曲前列素-诱导的经CFTR的Cl-流:
由于PDE4-同工型的抑制增强了曲前列素-诱导的cAMP累积,该操作预计增强了曲前列素对经囊性纤维化跨膜转导调节剂/Cl-通道(CFTR)的氯流的作用。该情况是这样的:前列环素引起CFTR的持续活化;所得的外向电流可通过将电压由-20跃至-80mV来检测。罗氟司特(以及其它PDE4抑制剂诸如异丁司特和RO20-1724)的加入引起电流的额外增加。该电流由CFTR传导,这是因为其由特异性抑制剂可逆地阻断。
结论
1)人气道上皮细胞表达若干受体,该受体可由曲前列素靶标以提升cAMP水平且由此活化人气道上皮细胞中的CFTR。
2)PDE4-同工型存在于人气道上皮细胞且PDE4-抑制剂有效地增加对曲前列素的响应。
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Claims (15)
1.用于预防或者治疗囊性纤维化的组合物,包含至少一种前列环素或者前列环素类似物或者其药用盐以及至少一种磷酸二酯酶(PDE)4抑制剂。
2.权利要求1的组合物,其中所述前列环素类似物选自曲前列素、伊洛前列素、西卡前列素或者贝前列素或者它们的药用盐。
3.权利要求1或者2的组合物,其中所述前列环素类似物选自曲前列素的酸衍生物、曲前列素的前药、曲前列素的多晶型或者曲前列素的异构体。
4.权利要求1-3中任一项的组合物,其中所述PDE4抑制剂选自Ro20-1724、异丁司特、罗氟司特及其N-氧化物、西洛司特、BAY19-8004、CC3、AWD12-281、SCH351591、西拉米特、吡拉米司特、CGH2466、松叶菊碱、咯利普兰、四羟黄酮和屈他维林。
5.组合物,包含曲前列素以及选自RO20-1724、罗氟司特和异丁司特的PDE4抑制剂。
6.权利要求1-5中任一项的组合物,其中含有选自PDE5、PDE7或者PDE8抑制剂的另外的PDE抑制剂。
7.权利要求6的组合物,其中所述PDE5抑制剂选自阿伐那非、Lodenafil、米罗那非、枸橼酸西地那非、他达那非、伐地那非或者优地那非。
8.权利要求6的组合物,其中所述PDE7和PDE8抑制剂选自双嘧达莫、BRL50481和PF-4957325。
9.权利要求1-8中任一项的组合物,其为药物组合物。
10.权利要求1-9中任一项的组合物,用于吸入。
11.权利要求1-9中任一项的组合物,用于静脉内或者皮下给药,或者为选自持续释放形式、片剂和胶囊剂的口服可用形式。
12.权利要求1-11中任一项的组合物,其中曲前列素或者其药用盐的有效量为至少1.0ng/kg体重。
13.增加细胞中cAMP水平的方法,其中使所述细胞与至少一种前列环素或者前列环素类似物以及至少一种PDE4抑制剂和任选地选自PDE5抑制剂、PDE7抑制剂或者PDE8抑制剂或者其药用盐的至少一种抑制剂接触。
14.治疗组合,包含至少一种前列环素或者前列环素类似物以及至少一种PDE4抑制剂和任选地选自PDE5抑制剂、PDE7抑制剂或者PDE8抑制剂的至少一种抑制剂,其中所述前列环素或者前列环素类似物以及PDE4抑制剂和任选地选自PDE5抑制剂、PDE7抑制剂和PDE8抑制剂的至少一种抑制剂以一起足以治疗和/或者预防至少一种与囊性纤维化相关的症状的量来提供。
15.权利要求14的治疗组合,其中配制所述前列环素或者前列环素类似物以及PDE4抑制剂和任选地选自PDE5抑制剂、PDE7抑制剂和PDE8抑制剂的至少一种抑制剂以用于吸入给药。
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PCT/EP2012/051880 WO2012107363A1 (en) | 2011-02-07 | 2012-02-03 | Novel composition for the treatment of cystic fibrosis |
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JP6542128B2 (ja) | 2013-01-11 | 2019-07-10 | コルセア ファーマ インコーポレイテッド | トレプロスチニルのプロドラッグ |
EP3587404B1 (en) | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
BR122019026637B1 (pt) | 2013-07-18 | 2023-09-26 | Mannkind Corporation | Formulações farmacêuticas de pó seco e método para a fabricação de uma formulação de pó seco |
US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
CN111108109A (zh) | 2017-09-20 | 2020-05-05 | 利奥制药有限公司 | 取代的二氢噻吩并嘧啶及其作为磷酸二酯酶抑制剂的用途 |
EP3498283A1 (en) | 2017-12-14 | 2019-06-19 | Ipsol AG | Glycosidic derivatives of treprostinil |
JP7203846B2 (ja) * | 2017-12-15 | 2023-01-13 | ユニオン・セラピューティクス・アクティエセルスカブ | 置換アゼチジンジヒドロチエノピリジンおよびホスホジエステラーゼ阻害剤としてのそれらの使用 |
CA3202852A1 (en) * | 2020-12-01 | 2022-06-09 | Reverspah Llc | Methods and compositions for treating chronic obstructive pulmonary disease, asthma, pneumonia, bronchitis, cystic fibrosis and pulmonary edema, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, a cute respiratory distress syndrome, and pulmonary arterial hypertension |
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