CN115003380A - 化合物及其用于治疗α1-抗胰蛋白酶缺乏症的用途 - Google Patents
化合物及其用于治疗α1-抗胰蛋白酶缺乏症的用途 Download PDFInfo
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- CN115003380A CN115003380A CN202080093537.0A CN202080093537A CN115003380A CN 115003380 A CN115003380 A CN 115003380A CN 202080093537 A CN202080093537 A CN 202080093537A CN 115003380 A CN115003380 A CN 115003380A
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及特定的式(1)的羧酸化合物,以及包含所述化合物的药物组合物。所述化合物可以是α1‑抗胰蛋白酶(A1AT)的诱导剂,并且可用于治疗疾病或障碍,例如α1‑抗胰蛋白酶缺乏症(A1AD或AATD)。
Description
本发明涉及某些羧酸及其医疗用途。
α1-抗胰蛋白酶(A1AT)是由肝脏产生并分泌到血液中的丝氨酸蛋白酶抑制剂超家族的成员。它抑制多种丝氨酸蛋白酶,尤其是嗜中性粒细胞弹性蛋白酶。当血液的A1AT水平较低时,嗜中性粒细胞弹性蛋白酶的过度活性会使肺组织降解,导致呼吸系统并发症,例如慢性阻塞性肺病(COPD)。
血液中A1AT的参考范围为0.9-2.3g/L。低于此水平是α1-抗胰蛋白酶缺乏症(A1AD或AATD)典型的,α1-抗胰蛋白酶缺乏症是由编码A1AT的SERPINA1基因中的突变引起的遗传疾病。Z突变是AATD最常见的原因,是A1AT(UniProtKB-P01009(A1AT_HUMAN))的第366位(对应于成熟蛋白(Z A1AT)的第342位)处的谷氨酸被赖氨酸替换。Z突变影响A1AT的折叠,导致只有一小部分获得天然/活性状态。其余部分作为错误折叠的蛋白质被清除,或作为稳定的聚合物在肝脏中积累。由于错误折叠,Z突变的纯合子携带者(ZZ)的血浆A1AT水平是正常的10-15%,使携带者易感于COPD。Z A1AT聚合物在肝细胞中的积累使携带者易感于肝硬化、肝癌和其它肝脏疾病。
目前对AATD肺部表现的治疗包括使用由献血者血浆制备的A1AT浓缩物进行强化治疗。美国FDA已批准使用四种A1AT产品:Prolastin、Zemaira、Glassia和Aralast。通过每周一次的静脉内输注给药。强化治疗已被证明减缓COPD的进展。AATD的肝脏表现(例如肝硬化和癌症)用类固醇和肝移植治疗。对于肝脏表现的改善治疗的研究方法包括抑制ZA1AT聚合和通过激活自噬提高聚合物的清除。对于肺和肝脏表现的改善治疗的研究方法旨在改善Z A1AT折叠和分泌。
Elliott等人(Protein Science,2000,9,1274–1281)描述了A1AT的X射线晶体结构,并确定了五个空腔,它们是合理药物设计的潜在目标,以开发影响Z A1AT聚合的药剂。
Parfrey等人(J.Biol.Chem.,2003,278,35,33060–33066)进一步定义了单个空腔,它是合理药物设计的潜在目标,以开发影响Z A1AT聚合的药剂。
Knaupp等人(J.Mol.Biol.,2010,396,375–383)表明双-ANS(4,4'-联苯胺-1,1'-联萘-5,5'-二磺酸盐)能够以1:1的化学计量和700nM的Kd与Z A1AT结合,但不能与野生型A1AT(M)结合。
Chang等人(J.Cell.Mol.Med.,2009,13,8B,2304-2316)报道了一系列抑制Z A1AT聚合的肽,包括Ac-TTAI-NH2。
Burrows等人(Proc.Nat.Acad.Sci.,2000,97,4,1796–1801)表明一系列非选择性伴侣分子(包括4-苯基丁酸、甘油和三甲胺氧化物)能够增加细胞上清液和小鼠模型中的ZA1AT水平。
Bouchecareilh等人(Journal of Biological Chemistry,2012,287,45,38265-38278)描述了使用组蛋白脱乙酰酶抑制剂,特别是SAHA(辛二酰苯胺异羟肟酸)来增加细胞的野生型(M)和ZA1AT的分泌。
Berthelier等人(PLOS ONE,May 11,2015)已经证明S-(4-硝基苄基)-6-硫鸟苷能够在体外阻止Z A1AT聚合。
Mallya等人(J.Med.Chem.,2007,50,22,5357–5363)描述了能够在体外阻断ZA1AT的聚合的一系列酚类,例如N-(4-羟基-3,5-二甲基苯基)-2,5-二甲基噻吩-3-磺酰胺。
Huntington(第13届蛋白酶、抑制剂和生物控制国际研讨会,2012年9月23日和第7届丝氨酸蛋白酶抑制剂生物学、结构和功能国际研讨会,2014年4月1日)讨论了来自Z A1AT的X射线晶体结构的空腔,它是合理药物设计的潜在目标,以开发影响Z A1AT聚合的药剂。
US8,436,013B2公开了多种能够在微摩尔范围内增加细胞的Z A1AT分泌的结构。
Angewandte Chemie International Edition vol 56,no 33,2017,9881-9885公开了1-((4-氯苯基)磺酰基)哌啶-4-羧酸作为除草剂。
Journal of Applicable Chemistry vol 2,no 6,2013,1501-1508公开了作为抗菌剂的1-(4-(三氟甲基)苯基磺酰基)哌啶-4-羧酸的合成。
US2011/0065707A1公开了1-(2-氯苯-磺酰基)-哌啶-4-羧酸作为试剂的用途。
EP0520336A2公开了1-(8-醌基(quinoyl)-磺酰基)-哌啶-4-羧酸。
WO2019/243841A1公开了氧代二氢吲哚-4-甲酰胺(oxoindoline-4-carboxamide)化合物作为α-1-抗胰蛋白酶的调节剂,并用于治疗与α-1-抗胰蛋白酶相关的疾病。
WO2020/081257A1公开了吡咯并-吲唑基-丙酸化合物作为α-1-抗胰蛋白酶的调节剂。
US2020/0361939A1进一步公开了吡咯并-吲唑基-丙酸化合物作为α-1-抗胰蛋白酶的调节剂。
本发明完成后,进行了基于1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸的结构的现有技术检索。通过检索事后确定的最接近的现有技术分子是外消旋化合物1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸(CAS登记号891392-68-0)。该化合物被列为可从Aurora、ChemDiv和FCHGroup商购获得的化合物,但未记录任何出版物。另一种接近的现有技术分子是1-(1-甲苯磺酰基-1,2,5,6-四氢吡啶-3-基)乙-1-酮(US9084782B2中的实施例16)。据称该化合物抑制血管生成并降低细胞胆固醇水平(尽管在US9084782B2中没有提供该化合物的生物学数据)。
根据本发明的一个方面,提供了式(1)的化合物(羧酸):
其中
·R1是任选取代或稠合的芳基或杂芳基环体系,
·m和n独立地为1、2或3,但不包括其中n和m均为1的组合,
·当m和n的组合产生手性中心时,任选地包括对映异构体和外消旋混合物二者,并且化合物是
·1-(喹啉-8-基磺酰基)哌啶-4-羧酸或
·1-((2-氯苯基)磺酰基)哌啶-4-羧酸或
·1-((3-氯苯基)磺酰基)哌啶-4-羧酸或
·1-((2,3-二氯苯基)磺酰基)哌啶-4-羧酸或
·(S)-1-((3-氟苯基)磺酰基)哌啶-3-羧酸或
·(S)-1-((3-氯苯基)磺酰基)哌啶-3-羧酸或
·(R)-1-((3-氟苯基)磺酰基)哌啶-3-羧酸或
·(R)-1-((3-氯苯基)磺酰基)哌啶-3-羧酸或
·1-((4-氯苯基)磺酰基)哌啶-4-羧酸或
·1-((2-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((3-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((4-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((2,5-双(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((2-(三氟甲氧基)苯基)磺酰基)哌啶-4-羧酸或
·(S)-1-((2-(三氟甲基)苯基)磺酰基)吡咯烷-3-羧酸或
·(R)-1-((2-(三氟甲基)苯基)磺酰基)吡咯烷-3-羧酸或
·(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸或
·(R)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸。
我们已经发现本发明的化合物令人惊讶地显示出在提高正确折叠的Z A1AT水平并因此具有提高的活性Z A1AT水平的方面非常有效,同时对野生型(M)A1AT或A1AT的Siiyama变体的分泌没有影响。
根据本发明还提供了根据权利要求1的具有手性中心的任何化合物的两种对映异构体的混合物,其中所述混合物是外消旋的或具有一种对映异构体超过另一种对映异构体。
本发明的化合物或混合物可以是药学上可接受的盐形式或结晶形式。
术语“药学上可接受的盐”是指本发明化合物的药学上可接受的单有机或无机盐。这可以包括衍生自碱的那些,例如氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钙、1-脱氧-2-(甲基氨基)-D-葡萄糖醇、氢氧化镁、氢氧化锌、氢氧化铝、氢氧化亚铁或氢氧化铁、氢氧化铵或有机胺如N-甲基葡糖胺、胆碱、精氨酸等。对于药学上可接受的盐的其它实例,可以参考Gould(1986,Int J Pharm 33:201-217)。
根据本发明的另一方面,提供了一种药物组合物,包含如本文所述的本发明化合物或混合物和药学上或治疗学上可接受的辅料或载体。
术语“药学上或治疗学上可接受的辅料或载体”是指不干扰活性成分的有效性或生物活性且对施用它的宿主(可以是人或动物)无毒的固体或液体填充剂、稀释剂或包封物质。取决于特定的施用途径,可以使用多种药学上可接受的载体,例如本领域熟知的那些。非限制性实例包括糖、淀粉、纤维素及其衍生物、麦芽、明胶、滑石、硫酸钙、植物油、合成油、多元醇、海藻酸、磷酸盐缓冲溶液、乳化剂、等渗盐水和无热原水。
根据本发明考虑了所有合适的施用方式。例如,药物的施用可以经由口腔、皮下、直接静脉内、缓慢静脉内输注、连续静脉内输注、静脉内或硬膜外患者自控镇痛(PCA和PCEA)、肌肉内、鞘内、硬膜外、脑池内(intracistemal)、腹膜内、透皮、局部、经粘膜、经颊、舌下、经粘膜、吸入、鼻内、心房内、鼻内、直肠或眼部途径。药物可以配制成离散的剂量单位并且可以通过药学领域熟知的任何方法制备。
考虑了所有合适的药物剂型。药物的施用可以例如以口服溶液剂和混悬剂、片剂、胶囊剂、锭剂、泡腾片剂、经粘膜膜剂、栓剂、经颊产品、口腔粘液保持产品、外用乳膏剂、软膏剂、凝胶剂、膜剂和贴剂、透皮贴剂、滥用威慑和抗滥用制剂、用于肠胃外使用的无菌溶液剂、混悬剂和贮库等,以立即释放、持续释放、延迟释放、控制释放、延长释放等的形式施用。
本发明的另一方面是如本文所定义的本发明化合物或混合物在制备用于治疗疾病或障碍的药物中的用途。
本发明的另一方面是用于作为Z A1AT分泌的诱导剂使用的本发明的化合物或混合物。
进一步提供了用于在治疗疾病或障碍中使用的如本文所定义的本发明化合物或混合物。
本发明还包括治疗疾病或障碍的方法,包括将如本文所定义的本发明化合物或混合物或药物组合物施用于有此需要的患者的步骤。
本发明还包括本发明化合物或混合物作为Z A1AT分泌的诱导剂的用途。该用途可以用于治疗疾病或障碍。另外或替代地,该用途可以是体外的,例如在体外测定中。
适合根据本发明相关方面治疗的疾病或障碍是以低血浆A1AT水平为特征的疾病或障碍,例如AATD。
本发明还提供式(1)的外消旋化合物在制备用于治疗疾病或障碍的药物中的用途,其中所述疾病或障碍是AATD。
还提供了式(1)的外消旋化合物作为Z A1AT分泌的诱导剂的用途。
本说明书中数字范围的使用旨在明确地在本发明的范围内包括该范围内的所有单个整数以及给定范围的最宽范围内的上限和下限数字的所有组合。
如本文所用,术语“包括/包含”应理解为表示包括/包含和由……组成二者。因此,当本发明涉及“包含作为活性成分的化合物”的药物组合物时,该术语旨在涵盖其中可以存在其它活性成分的组合物以及仅由所定义的一种活性成分组成的组合物。
除非另有定义,否则此处使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解相同的含义。类似地,此处提及的所有出版物、专利申请、所有专利和所有其它参考文献均以引用的方式整体并入(在法律允许的情况下)。
现在将描述本发明的特定非限制性实施例。
图1是显示(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸对表达人Z A1AT的小鼠(huZ小鼠)中Z A1AT水平的影响的图。小鼠用溶媒、5、15和50mg/kg的(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸通过口服灌胃法每天处理两次,连续14天。在第-12、-7和-5天取血并制备血浆以确定人Z A1AT的循环基础水平。在研究的最后三天(第12、13和14天)收集的血浆样品用于确定与基础水平相比(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸处理对循环人Z A1AT水平的影响。x轴是(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸的处理剂量,单位为mg/kg;y轴是每个处理组的与基线水平相比人Z A1AT的平均百分比水平(即A1AT%基线)。
实验
一般方法
使用以下合成程序制备式1的化合物。
将羧酸(1当量)、氢氧化钾(1当量)和碳酸钾(2当量)添加到水中并搅拌。添加磺酰氯(1当量)并将反应在室温搅拌3小时。将反应冷却至0℃并用2M盐酸酸化,得到白色沉淀。将该沉淀干燥并用正戊烷研磨,得到式(1)的化合物。
实施例1:1-(喹啉-8-基磺酰基)哌啶-4-羧酸
使用一般方法和1-喹啉-8-基磺酰氯和哌啶-4-羧酸制备实施例1的化合物。
1H NMR(400MHz,d6 DMSO)δ12.26(1H,s),9.07(1H,s),8.54(1H,d),8.36(1H,d),8.30(1H,d),7.74(1H,m),7.70(1H,m),3.81(2H,m),2.82(2H,m),2.31(1H,m),1.82(2H,m),1.44(1H,m)。
实施例2:1-((2-氯苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(2-氯苯基)磺酰氯和哌啶-4-羧酸制备实施例2的化合物。
1H NMR(400MHz,d6 DMSO)δ12.38(1H,br s),7.97(1H,d),7.88(2H,m),7.56(1H,m),3.60(2H,m),2.83(2H,t),2.40(1H,m),1.86(2H,m),1.48(2H,m)。
实施例3:1-((3-氯苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(3-氯苯基)磺酰氯和哌啶-4-羧酸制备实施例3的化合物。
1H NMR(400MHz,CDCl3)δ7.77(1H,s),7.76(1H,d),7.63(1H,m),7.60(1H,m),3.68(2H,m),2.55(2H,t),2.37(1H,m),2.02(2H,m),1.86(2H,m)。
实施例4:1-((2,3-二氯苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(2,3-二氯苯基)磺酰氯和哌啶-4-羧酸制备实施例4的化合物。
1H NMR(400MHz,d6 DMSO)δ12.36(1H,br s),7.97(2H,d),7.59(1H,m),3.64(2H,m),2.90(2H,t),2.43(1H,m),1.80(2H,m),1.54(2H,m)。
实施例5:(S)-1-((3-氟苯基)磺酰基)哌啶-3-羧酸
使用一般方法和1-(3-氟苯基)磺酰氯和(S)-哌啶-3-羧酸制备实施例5的化合物。
1H NMR(400MHz,CD3OD)δ7.52(2H,m),7.48(1H,m),7.44(1H,m),3.73(1H,d),3.53(1H,d),2.60(3H,m),1.97(1H,m),1.81(1H,m),1.59(1H,m),1.50(1H,m)。
实施例6:(S)-1-((3-氯苯基)磺酰基)哌啶-3-羧酸
使用一般方法和1-(3-氯苯基)磺酰氯和(S)-哌啶-3-羧酸制备实施例6的化合物。
1H NMR(400MHz,CD3OD)δ7.79(1H,s),7.68(2H,m),7.62(1H,m),3.72(1H,d),3.51(1H,d),2.60(3H,m),1.97(1H,m),1.81(1H,m),1.58(1H,m),1.51(1H,m)。
实施例7:(R)-1-((3-氟苯基)磺酰基)哌啶-3-羧酸
使用一般方法和1-(3-氟苯基)磺酰氯和(R)-哌啶-3-羧酸制备实施例7的化合物。
1H NMR(400MHz,CD3OD)δ7.52(2H,m),7.48(1H,m),7.44(1H,m),3.73(1H,d),3.53(1H,d),2.60(3H,m),1.97(1H,m),1.81(1H,m),1.59(1H,m),1.50(1H,m)。
实施例8:(R)-1-((3-氯苯基)磺酰基)哌啶-3-羧酸
使用一般方法和1-(3-氯苯基)磺酰氯和(R)-哌啶-3-羧酸制备实施例8的化合物。
1H NMR(400MHz,CD3OD)δ7.79(1H,s),7.68(2H,m),7.62(1H,m),3.73(1H,d),3.53(1H,d),2.60(3H,m),1.97(1H,m),1.81(1H,m),1.59(1H,m),1.50(1H,m)。
实施例9:1-((4-氯苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(4-氯苯基)磺酰氯和哌啶-4-羧酸制备实施例9的化合物。
1H NMR(400MHz,d6 DMSO)δ12.32(1H,s),7.73(4H,m),3.47(2H,m),2.44(2H,m),2.28(1H,m),1.86(2H,m),1.57(2H,m)。
实施例10:1-((2-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(2-(三氟甲基)苯基)磺酰氯和哌啶-4-羧酸制备实施例10的化合物。
1H NMR(400MHz,d6 DMSO)δ12.36(1H,s),8.03(2H,m),7.90(2H,m),3.61(2H,m),2.85(2H,m),2.41(1H,m),1.90(2H,m),1.55(2H,m)。
实施例11:1-((3-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(3-(三氟甲基)苯基)磺酰氯和哌啶-4-羧酸制备实施例11的化合物。
1H NMR(400MHz,d6 DMSO)δ12.33(1H,s),8.13(1H,m),8.07(1H,m),7.95(1H,m),7.90(1H,m),3.53(2H,m),2.45(2H,m),2.32(1H,m),1.89(2H,m),1.57(2H,m)。
实施例12:1-((4-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(4-(三氟甲基)苯基)磺酰氯和哌啶-4-羧酸制备实施例12的化合物。
1H NMR(400MHz,d6 DMSO)δ8.00(2H,m),7.92(2H,m),3.20(2H,m),2.54(2H,m),1.70(3H,m),1.57(2H,m)。
实施例13:1-((2,5-双(三氟甲基)苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(2,5-双(三氟甲基)苯基)磺酰氯和哌啶-4-羧酸制备实施例13的化合物。
1H NMR(400MHz,d6 DMSO)δ12.36(1H,s),8.30(2H,m),8.24(1H,s),3.65(2H,m),2.87(2H,m),2.43(1H,m),1.89(2H,m),1.54(2H,m)。
实施例14:1-((2-(三氟甲氧基)苯基)磺酰基)哌啶-4-羧酸
使用一般方法和1-(2-(三氟甲氧基)苯基)磺酰氯和哌啶-4-羧酸制备实施例14的化合物。
1H NMR(400MHz,d6 DMSO)δ12.33(1H,s),7.93(1H,m),7.83(1H,m),7.62(2H,m),3.56(2H,m),2.71(2H,m),2.36(1H,m),1.87(2H,m),1.52(2H,m)。
实施例15:(S)-1-((2-(三氟甲基)苯基)磺酰基)吡咯烷-3-羧酸
使用一般方法和1-(2-(三氟甲基)苯基)磺酰氯和(S)-吡咯烷-3-羧酸制备实施例15的化合物。
1H NMR(400MHz,d6 DMSO)δ12.62(1H,br s),8.05(2H,m),7.90(2H,m),3.48(2H,m),3.38(2H,m),3.15(1H,m),2.11(2H,m)。
实施例16:(R)-1-((2-(三氟甲基)苯基)磺酰基)吡咯烷-3-羧酸
使用一般方法和1-(2-(三氟甲基)苯基)磺酰氯和(R)-吡咯烷-3-羧酸制备实施例16的化合物。
1H NMR(400MHz,d6 DMSO)δ12.62(1H,br s),8.05(2H,m),7.90(2H,m),3.48(2H,m),3.38(2H,m),3.15(1H,m),2.11(2H,m)。
实施例17:(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸
(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸使用以下合成程序制备。
将(S)-哌啶-3-羧酸(1g,7.7mmol)、氢氧化钾(434mg,7.7mmol)和碳酸钾(2.14g,15.4mmol)添加到水(20ml)中并搅拌。添加2-(三氟甲基)苯磺酰氯(1.89g,7.7mmol)并将反应在室温搅拌3小时。将反应冷却至0℃并用2M盐酸酸化,得到白色沉淀。将该沉淀干燥并用正戊烷研磨,得到(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸。
Tlc Rf 0.370%乙酸乙酯于己烷中。
m/z:337.98(计算值338.03)
1H NMR(400MHz,d6 DMSO)δ12.33(1H,s),8.04(2H,m),7.90(2H,m),3.69(1H,dd),3.50(1H,dd),2.93(1H,m),2.81(1H,m),1.91(1H,m),1.72(1H,m),1.50(2H,m)。
实施例18:(R)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸
(R)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸以与(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸相同的方式制备,但使用(R)-哌啶-3-羧酸。
Tlc Rf 0.370%乙酸乙酯于己烷中。
m/z:338.03(计算值338.03)
1H NMR(400MHz,d6 DMSO)δ12.53(1H,s),8.04(2H,m),7.90(2H,m),3.69(1H,dd),3.49(1H,dd),2.93(1H,m),2.81(1H,m),1.90(1H,m),1.72(1H,m),1.49(2H,m)。
实施例19:实施例1-18化合物在使用HEK-Z细胞的A1AT细胞分泌测定中的活性
方法
将HEK-Z细胞(稳定转染有人Z A1AT基因的人胚肾细胞系)铺在96孔板(3.0×105个细胞/ml,200μl培养基/孔)中,在包含5%CO2的潮湿环境中于37℃过夜。孵育后,将细胞用200μl无血清培养基洗涤3次,并更换培养基以使用包含溶媒、10μM辛二酰苯胺异羟肟酸(SAHA)或实施例1-18化合物(浓度为10、33、100和333nM)的无血清培养基一式四份地以200μl的终体积在37℃培养箱中处理48小时。在孵育步骤结束时,从孔中取出上清液,在4℃以1000×g离心10分钟,并通过ELISA(人丝氨酸蛋白酶抑制剂A1/α1-抗胰蛋白酶双重ELISA,R&D Systems,DY1268)按照制造商的说明测定人A1AT水平。
简而言之,将96孔板在室温用人A1AT捕获抗体包被过夜(由储液1:180稀释,100μl终体积/孔)。然后去除捕获抗体并用300μl洗涤缓冲液(PBS中的0.05%Tween 20)洗涤孔3次,然后在每个孔中将200μl试剂稀释液(PBS中的25%Tween 20)在室温孵育1小时。然后将稀释的样品、标准品(125、250、500、1000、2000、4000和8000pg/ml A1AT)或空白一式两份地添加到每个孔中,用封板器覆盖板并在室温放置2小时。在样品孵育步骤结束时,去除样品并如前所述洗涤所有孔,并将100μl检测抗体(从储液1:180稀释)添加到每个孔中,并在室温再孵育2小时。与检测抗体孵育后,去除上清液并如前所述洗涤孔,然后将100μl链霉亲和素-HRP溶液(从储液1:200稀释)添加到每个孔中,在黑暗中保持20分钟。之后,添加50μl终止溶液(2M H2SO4),并使用酶标仪在450nm处读取每个孔的光密度(OD),并从每个孔中减去570nm空白。使用GraphPad Prism 7构建4参数逻辑曲线,并通过从标准曲线插值并乘以适当的稀释因子来确定每个样品中的A1AT浓度。
结果
通过ELISA测量由转染的HEK-EBNA细胞分泌到培养基中的人A1AT的量。10μM的SAHA用作所有体外A1AT分泌实验的阳性对照。
表1中的数据表明实施例1-18的化合物以剂量依赖性方式增加HEK-Z细胞的人ZA1AT分泌,如通过ELISA测量的。
表1
实施例20:实施例1-18化合物在使用HEK-M细胞的A1AT细胞分泌测定中的活性
方法
将HEK-M细胞(稳定转染有M A1AT基因的人胚肾细胞系)铺在96孔板(3.0×105个细胞/ml,200μl培养基/孔)中,在包含5%CO2的潮湿环境中于37℃过夜。孵育后,将细胞用200μl无血清培养基洗涤3次,并将培养基更换为包含溶媒、10μM辛二酰苯胺异羟肟酸(SAHA)或实施例1-16化合物的无血清培养基一式六份地以200μl的终体积在37℃培养箱中48小时。在孵育步骤结束时,从孔中取出上清液,在4℃以1000×g离心10分钟,并通过ELISA(人丝氨酸蛋白酶抑制剂A1/α1-抗胰蛋白酶双重ELISA,R&D Systems,DY1268)按照制造商的说明测定人A1AT水平。
简而言之,将96孔板在室温用人A1AT捕获抗体包被过夜(由储液1:180稀释,100μl终体积/孔)。然后去除捕获抗体并用300μl洗涤缓冲液(PBS中的0.05%Tween 20)洗涤孔3次,然后在每个孔中将200μl试剂稀释液(PBS中的25%Tween 20)在室温孵育1小时。然后将稀释的样品、标准品(125、250、500、1000、2000、4000和8000pg/ml A1AT)或空白一式两份地添加到每个孔中,用封板器覆盖板并在室温放置2小时。在样品孵育步骤结束时,去除样品并如前所述洗涤所有孔,并将100μl检测抗体(从储液1:180稀释)添加到每个孔中,并在室温再孵育2小时。与检测抗体孵育后,去除上清液并如前所述洗涤孔,然后将100μl链霉亲和素-HRP溶液(从储液1:200稀释)添加到每个孔中,在黑暗中保持20分钟。之后,添加50μl终止溶液(2M H2SO4),并使用酶标仪在450nm处读取每个孔的光密度(OD),并从每个孔中减去570nm空白。使用GraphPad Prism 7构建4参数逻辑曲线,并通过从标准曲线插值并乘以适当的稀释因子来确定每个样品中的A1AT浓度。
结果
通过ELISA测量由转染的HEK-EBNA细胞分泌到培养基中的人M A1AT的量。10μM的SAHA用作所有体外A1AT分泌实验的阳性对照。实施例1、3、4、10、17和18的化合物在10μM时不会导致HEK-M细胞的人M A1AT的分泌增加。
实施例21:实施例1和17化合物在使用HEK-Siiyama细胞的A1AT细胞分泌测定中的活性
在患有AATD的日本男性中鉴定了罕见的Siiyama突变(Ser 53突变为Phe,成熟A1AT编号)(Seyama等人J Biol Chem(1991)266:12627-32)。Ser53是保守的丝氨酸蛋白酶抑制剂残基之一,并且被认为对A1AT分子内部核心的组织很重要。蛋白质保守骨架上从不带电的极性氨基酸变化为大的非极性氨基酸影响了Siiyama A1AT的折叠和细胞内加工。
方法
将HEK-Siiyama细胞(稳定转染有人Siiyama A1AT基因的人胚肾细胞系)铺在96孔板(3.0×105个细胞/ml,200μl培养基/孔)中,在包含5%CO2的潮湿环境中于37℃过夜。孵育后,将细胞用200μl无血清培养基洗涤3次,将培养基更换为包含溶媒、10μM辛二酰苯胺异羟肟酸(SAHA)或实施例1的化合物(1和10μM)的无血清培养基一式八份地以200μl的终体积在37℃培养箱中48小时。在孵育步骤结束时,从孔中取出上清液,在4℃以1000×g离心10分钟,并通过ELISA(人丝氨酸蛋白酶抑制剂A1/α1-抗胰蛋白酶双重ELISA,R&D Systems,DY1268)按照制造商的说明测定人A1AT水平。
简而言之,将96孔板在室温用人A1AT捕获抗体包被过夜(由储液1:180稀释,100μl终体积/孔)。然后去除捕获抗体并用300μl洗涤缓冲液(PBS中的0.05%Tween 20)洗涤孔3次,然后在每个孔中将200μl试剂稀释液(PBS中的25%Tween 20)在室温孵育1小时。然后将稀释的样品、标准品(125、250、500、1000、2000、4000和8000pg/ml A1AT)或空白一式两份地添加到每个孔中,用封板器覆盖板并在室温放置2小时。在样品孵育步骤结束时,去除样品并如前所述洗涤所有孔,并将100μl检测抗体(从储液1:180稀释)添加到每个孔中,并在室温再孵育2小时。与检测抗体孵育后,去除上清液并如前所述洗涤孔,然后将100μl链霉亲和素-HRP溶液(从储液1:200稀释)添加到每个孔中,在黑暗中保持20分钟。之后,添加50μl终止溶液(2M H2SO4),并使用酶标仪在450nm处读取每个孔的光密度(OD),并从每个孔中减去570nm空白。使用GraphPad Prism 7构建4参数逻辑曲线,并通过从标准曲线插值并乘以适当的稀释因子来确定每个样品中的A1AT浓度。
结果
通过ELISA测量由转染的HEK-EBNA细胞分泌到培养基中的人Siiyama A1AT的量。10μM的SAHA用作所有体外A1AT人分泌实验的阳性对照。如通过ELISA测量的,实施例1和17的示例性化合物在1或10μM时不刺激HEK-Siiyama细胞分泌Siiyama A1AT。相反,阳性对照10μM SAHA刺激了Siiyama A1AT分泌的增加。
实施例22:实施例1和17的化合物在表达人Z的小鼠(huZ小鼠)中的活性
huZ小鼠(也称为PiZZ小鼠)是由两个独立的团队开发的包含人A1AT基因的Z变体的多个拷贝的转基因小鼠品系(Dycaico等人Science(1988)242:1409-12)和Carlson等人J.ClinInvest(1989)83:1183-90)。HuZ小鼠在C57Bl/6背景上并在肝组织中表达人Z A1AT蛋白。本研究中使用的小鼠来自Carlson及其同事的后代(转基因系Z11.03)。HuZ小鼠已被用作评估本发明的示例性化合物对增加血浆中的循环Z A1AT水平的影响或化合物对ZA1AT聚合物在肝脏中的积累和相关肝脏病理学的影响的工具。
每天两次通过口服灌胃法用溶媒或实施例1或17的化合物以5、15或50mg/kg处理基础人Z A1AT血浆水平在200-600μg/ml之间的HuZ小鼠(n=4/组;雄性或雌性),连续14天。小鼠可以以任意采食的方式获取食物(标准小鼠食物SAFE饮食)和水。在研究的第14天,每只小鼠在终末程序前一小时给药。在给药前第-12、-7和-5天,以及第12、13和14给药天,从每只小鼠的尾静脉取血。将血液收集到包含EDTA的微量采血管中,并通过在4℃以2700×g离心10分钟来制备血浆。将血浆等分并储存在-80℃用于生物分析。来自给药前天-12、-7和-5的血浆样品用于确定每只小鼠的人Z A1AT的平均基础水平。在研究的最后三个给药日(第12、13和14天)收集的血浆样品用于通过测量人Z A1AT水平并与每只小鼠的基础水平比较来确定实施例1或17的化合物对人Z A1AT分泌的影响。通过ELISA(人丝氨酸蛋白酶抑制剂A1/α1-抗胰蛋白酶双重ELISA,R&D Systems,DY1268)按照制造商的说明测量小鼠血浆样品中的人Z A1AT水平。
简而言之,将96孔板在室温用人A1AT捕获抗体包被过夜(由储液1:180稀释,100μl终体积/孔)。然后去除捕获抗体并用300μl洗涤缓冲液(PBS中的0.05%Tween 20)洗涤孔3次,然后在每个孔中将200μl试剂稀释液(PBS中的25%Tween 20)在室温孵育1小时。然后将稀释的样品、标准品(125、250、500、1000、2000、4000和8000pg/ml A1AT)或空白一式两份地添加到每个孔中,用封板器覆盖板并在室温放置2小时。在样品孵育步骤结束时,去除样品并如前所述洗涤所有孔,并将100μl检测抗体(从储液1:180稀释)添加到每个孔中,并在室温再孵育2小时。与检测抗体孵育后,去除上清液并如前所述洗涤孔,然后将100μl链霉亲和素-HRP溶液(从储液1:200稀释)添加到每个孔中,在黑暗中保持20分钟。之后,添加50μl终止溶液(2M H2SO4),并使用酶标仪在450nm处读取每个孔的光密度(OD),并从每个孔中减去570nm空白。使用GraphPad Prism 7构建4参数逻辑曲线,并通过从标准曲线插值并乘以适当的稀释因子来确定每个样品中的A1AT浓度。
结果
在huZ小鼠模型中评估实施例1或17的化合物对人Z A1AT循环水平的影响。
与huZ小鼠中的基线水平相比,实施例1和17的化合物刺激了人Z A1AT的分泌。图1显示了实施例17化合物在每个处理剂量下的数据。
Claims (14)
1.式(1)的化合物
其中
·R1是任选取代或稠合的芳基或杂芳基环体系,
·m和n独立地为1、2或3,但不包括其中n和m均为1的化合物,
并且所述式(1)的化合物是
·1-(喹啉-8-基磺酰基)哌啶-4-羧酸或
·1-((2-氯苯基)磺酰基)哌啶-4-羧酸或
·1-((3-氯苯基)磺酰基)哌啶-4-羧酸或
·1-((2,3-二氯苯基)磺酰基)哌啶-4-羧酸或
·(S)-1-((3-氟苯基)磺酰基)哌啶-3-羧酸或
·(S)-1-((3-氯苯基)磺酰基)哌啶-3-羧酸或
·(R)-1-((3-氟苯基)磺酰基)哌啶-3-羧酸或
·(R)-1-((3-氯苯基)磺酰基)哌啶-3-羧酸或
·1-((4-氯苯基)磺酰基)哌啶-4-羧酸或
·1-((2-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((3-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((4-(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((2,5-双(三氟甲基)苯基)磺酰基)哌啶-4-羧酸或
·1-((2-(三氟甲氧基)苯基)磺酰基)哌啶-4-羧酸或
·(S)-1-((2-(三氟甲基)苯基)磺酰基)吡咯烷-3-羧酸或
·(R)-1-((2-(三氟甲基)苯基)磺酰基)吡咯烷-3-羧酸或
·(S)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸或
·(R)-1-((2-(三氟甲基)苯基)磺酰基)哌啶-3-羧酸。
2.根据权利要求1的具有手性中心的任何化合物的两种对映异构体的混合物,其中所述混合物是外消旋的或具有一种对映异构体超过另一种对映异构体。
3.根据权利要求1或权利要求2所述的化合物或混合物,为药学上可接受的盐形式。
4.一种药物组合物,包含根据权利要求1-3中任一项所述的化合物或混合物和药学或治疗学上可接受的辅料或载体。
5.根据权利要求1-3所述的化合物或混合物在制备用于治疗疾病或障碍的药物中的用途。
6.根据权利要求1-3所述的化合物或混合物,用于在治疗疾病或障碍中使用。
7.根据权利要求1-3所述的化合物或混合物,用于作为Z A1AT分泌的诱导剂使用。
8.一种治疗疾病或障碍的方法,包括将根据权利要求1-3所述的化合物或混合物或根据权利要求4所述的药物组合物施用于有此需要的患者的步骤。
9.根据权利要求1-3所述的化合物或混合物在治疗疾病或障碍中的用途。
10.根据权利要求9所述的用途,作为Z A1AT分泌的诱导剂。
11.根据权利要求9或权利要求10所述的用途,其中所述用途是体外的。
12.根据权利要求5所述的用途、根据权利要求6使用的所述化合物或混合物、根据权利要求8所述的治疗方法、或根据权利要求9-11中任一项所述的用途,其中所述疾病或障碍是AATD。
13.式(1)的外消旋化合物在制备用于治疗疾病或障碍的药物中的用途,其中所述疾病或障碍是AATD。
14.式(1)的外消旋化合物作为Z A1AT分泌的诱导剂的用途。
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