CN1427718A - 治疗copd的药物化合物 - Google Patents
治疗copd的药物化合物 Download PDFInfo
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Abstract
MPO抑制剂在治疗COPD中的应用。
Description
本发明涉及利用某些药物化合物来治疗COPD。
COPD是发病率和死亡率的主要原因。一个关键的病因学因素是吸烟。很显然,吸烟者的MPO水平提高(Dash等人,Blood.,1991,72,1619;Bridges等人.,Eur.J.Respir.Dis.,1985,67,84)。此外,有情况证明,人受试者肺病的严重性与MPO水平有关(Hill等人.Am.J.Respir.Crit.Care.,1999,160,893;Keatings&Barnes.,Am.J.Respir.Crit.Care.,1997,155,449;Regelmann等人.,Pediatric.Pulmonol.,1995,19,1;Linder等人.,Am Rev.Respir.Dis.,1993,148,1226)。脊髓过氧化物酶(Myeloperoxidase)是在产生毒性次氯酸和自由基中发挥重要作用的血红素蛋白质,它可在细胞损伤和炎症中涉及到(Kettle&Winterbourn.,Curr.Opin.Hematol.,2000,7,53)。该蛋白质已在各种不同的疾病中涉及到(Klebanoff.,Pro.Assoc.Am.Physicians.,1999,111,383)。具有作为MPO抑制剂活性的化合物是本领域已知的(Kettle&Winterbourn.,Biochem.Pharmacol.,1991,41,10;Bozeman等人,Biochem.Pharmacol.,1992,44,553)。例如,已知是MPO抑制剂的化合物达普宋已与各种疾病包括通常所提到的炎性疾病如哮喘的治疗联系起来(Berloe等人,J.Allergy Clin.Immunol.,1991,87,710)。有趣的是,尚没有特别提到利用任何通过合成方法衍生的MPO化学抑制剂来治疗COPD。
现有用于治疗COPD的药物不都是完全有效的。需要新的和更好的药物来处理正在日益上升的COPD事件(Peleman等人.Curr.Opin.Cardiovas.Pulmonary.Renal.Invest.Drugs.,1999,1,491)。现意外地发现,具有作为MPO抑制剂活性的化合物预期将有效地用于治疗COPD。
因此,一方面本发明提供MPO抑制剂在治疗COPD中的应用。可以理解,本发明MPO抑制剂可在治疗学方面应用或作为预防药应用。
特别适宜的化合物包括本领域已知的MPO抑制剂。
优选的化合物包括以下所列出的那些:
伯氨喹 达普宋 氨基比林甲芬那酸 磺胺吡啶 丙基硫尿嘧啶磺胺嘧啶 磺胺异噁唑 磺胺胍磺胺硝苯 磺胺 N-1-(2-噻唑基)磺胺双氯芬酸 吡罗昔康 香草醛对氨基苯甲酸乙酯 3-氨基酸乙酯 对氨基苯甲酰胺褪黑激素 6-甲氧基吲哚 吲哚3-甲基吲哚 5-甲氧基吲哚 5-甲氧基色醇5-甲氧基色胺其他优选的化合物包括下列化合物:异烟肼NITECAPONE5-氨基水杨酸苯肼D-青霉胺
硫普罗宁
雷琐辛
槲皮黄酮
芦丁
奎纳克林
BAKUCHIOL
上述化合物可以以游离碱和可药用盐形式使用。适宜的盐包括所有已知的可药用盐如酸加成盐如盐酸盐和苹果酸盐。
优选的化合物包括伯氨喹啉、磺胺、达普宋和磺胺吡啶,特别是达普宋。
本发明也提供治疗或预防COPD的方法,它包括给予患者MPO抑制剂或其可药用盐,特别是给予伯氨喹、达普宋、氨基比林、piceatannol、甲芬那酸、磺胺吡啶、磺胺、丙基硫尿嘧啶、磺胺嘧啶、磺胺异噁唑(sulfisoxazole)、磺胺胍、磺胺硝苯(sulfanitran)、磺胺、N-1(2-噻唑基)磺胺、双氯芬酸、吡罗昔康、香草醛、对氨基苯甲酸乙酯、3-氨基酸乙酯、对氨基苯甲酰胺、褪黑激素、6-甲氧基吲哚、吲哚、3-甲基吲哚、5-甲氧基吲哚、5-甲氧基色醇、5-甲氧基色胺及其可药用盐。
另一方面,本发明提供MPO抑制剂,特别是以上所提到的化合物在生产治疗或预防COPD药物中的应用。
适宜的每日剂量范围大约为0.1mg/kg-100mg/kg。按照惯例,单位剂量可以每日给药一次或一次以上,例如每日2,3或4次,通常每日1或2次。对于100mg或300mg的达普宋或丙基硫尿嘧啶来说,典型的给药方案分别为每日1次或2次。
包含本发明MPO抑制剂的药物组合物方便的形式可以为用于口服给药的片剂、丸剂、胶囊剂、糖浆剂、粉剂或颗粒剂;用于非肠道给药的灭菌非肠道或皮下溶液、悬浮液或用于直肠给药的栓剂,所有这些都是本领域公知的。
下列实施例用于说明本发明。实施例1
本文描述体外MPO测定,该测定用于评估酶活性的抑制作用。MPO测定基本上设计为测定次氯酸(HOCl)的产生,次氯酸是由体内酶产生的重要的生理产物。下面描述所述测定反应的要点:
2.
3.
在20mM pH6.5磷酸盐缓冲液中的反应混合物包含2.5nM MPO(由Planta提供的人类酶的纯品)、100uM H2O2、140mM NaCl、10mM牛磺酸、20uM酪氨酸和1%的化合物溶剂DMSO。在开始与H2O2反应前,将化合物与MPO酶一起在缓冲剂预孵育15分钟。整个反应在室温下、在96-孔平皿中进行10分钟。通过加入阻化/展开剂终止反应,所述阻化/展开剂最终浓度为冰醋酸(400mM)、KI(100uM)和TMB的二甲基甲酰胺溶液(10mM)。除非另外说明,所有试验浓度重复测定,至少分别测定2次,n=2,化合物抑制剂的浓度由pIC50,即-log IC50表示。
已测试各种化合物的抗MPO作用。可以看出,达普宋是所测试砜/磺胺最有效的抑制剂。吲哚和其他化合物也有效地阻断人类MPO产生HOCl。所得到的关于砜/磺胺、吲哚和其他化合物的数据分别显示于表1、2和3。
表1:砜/磺胺对人类MPO-HOCl产生的抑制作用
化合物 | pI50 |
达普宋 | 6.2 |
N-1(2噻唑基)-磺胺 | 6.0 |
磺胺 | 6.0 |
磺胺吡啶 | 5.7 |
磺胺胍 | 5.5 |
磺胺异噁唑 | 5.2 |
磺胺嘧啶 | 5.2 |
磺胺硝苯 | 5.1 |
表2:吲哚对人类MPO-HOCl产生的抑制作用
化合物 | pI50 |
5-甲氧基色醇 | 6.3 |
5-甲氧基色胺 | 6.2 |
褪黑激素 | 6.1 |
3-甲基吲哚 | 5.9 |
6-甲氧基吲哚 | 5.8 |
吲哚 | 5.7 |
5-甲氧基吲哚 | 5.6 |
表3:人类MPO-HOCl产生的抑制作用
实施例2
化合物 | pI50 |
氨基苯甲酸乙酯 | 6.2 |
3-氨基苯甲酸乙酯 | 6.2 |
对氨基苯甲脒 | 5.6 |
吡罗昔康 | 5.6(n=1) |
双氯芬酸 | 5.4 |
香草醛 | 5.1 |
本文描述利用人类嗜中性白细胞功能分析来测定MPO对HOCl产生的抑制作用。该分析可以检测受激(例如PMA、LPS、fMLP、zymozan)的人类嗜中性白细胞。通过在Polymorphprep(Nycomed)上密度离心,由新鲜肝素化血中提纯人类嗜中性白细胞。这些嗜中性白细胞在提纯后立即使用。标准反应混合物包含下列成分:2×106个嗜中性白细胞、140mM NaCl、5mM牛磺酸、0.5mM MgCl2、1mM CaCl2和1mg/ml葡萄糖。在DMSO中配制试验化合物并加到测报中,DMSO的最终浓度为0.5%。在加到PMA兴奋剂(1ug/ml)前,将试验化合物与嗜中性白细胞一起在37℃下孵育15分钟。然后在37℃下再孵育30分钟。在孵育结束后,通过离心收集上清液并通过使用上述阻化/展开剂测定HOCl。所有化合物测试2次,两个不同的供体至少分别测定两次n=2。
某些抑制剂的数据显示于表4中。
表4:受激人类嗜中性白细胞对HOCl产生的抑制作用
嗜中性白细胞产生HOCl | pIC50 |
伯氨喹 | 4.9 |
磺胺 | 4.8 |
达普宋 | 4.7 |
磺胺吡啶 | 4.5 |
我们也表明,在所述测定条件和所使用抑制剂浓度下,通过评定受损嗜中性白细胞释放乳糖脱氢酶可知,人类嗜中性白细胞不受细胞毒性的影响。如Boehringer Mannheim GmbH,Sandhofer Strabe 116,D-68305 Mannheim,Germany(Cytotoxicity Detection Kit-LDH-Cat No:1 644 793)所述测定乳糖脱氢酶活性。
实施例3
有几种可用于测试MPO抑制剂的COPD动物模型。这些模型已在Snider(Chest.,1992,101,74S)和Shapiro(Am.J.Respir.CellMol.Biol.,2000,22,4)的评论中提到。在我们的研究中,我们优选LPS-和/或吸烟-诱导肺损伤啮齿动物模型。可在LPS和/或吸烟激发前给予(通过下列任一途径:ip、po、iv、sc或气雾剂)小鼠或大鼠MPO抑制剂。间隔适当的时间后,将动物处死并评价肺损伤(类似于Faffe等人所报道的工作,Eur.Respir.J.,2000,15,85;Suntres&Shek.,Biochem.Pharmacol.,2000,59,1155;Vanhelden等人,Exp.Lung.Res.,1997,23,297)。然后,测定肺灌洗液(BAL)、肺组织、嗜中性白细胞和全血的MPO活性。可分析血样的炎性细胞和细胞因子(例如TNFα)。可评价肺细胞损伤的组织化学生物化学指标(例如氯化蛋白、乳糖脱氢酶、碱性磷酸酶)。测定MPO抑制剂抵抗MPO减少/预防肺损伤能力的功效。预期,在这些模型中,这些MPO抑制剂将是治疗学或预防学上有效的。
Claims (8)
1.MPO抑制剂在治疗COPD中的应用。
2.权利要求1的应用,其中具有MPO抑制剂活性的化合物为伯氨喹、达普宋、氨基比林、piceatannol、甲芬那酸、磺胺吡啶、磺胺、丙基硫尿嘧啶、磺胺嘧啶、磺胺异噁唑、磺胺胍、磺胺硝苯、磺胺、N-1(2-噻唑基)磺胺、双氯芬酸、吡罗昔康、香草醛、对氨基苯甲酸乙酯、3-氨基酸乙酯、对氨基苯甲酰胺、褪黑激素、6-甲氧基吲哚、吲哚、3-甲基吲哚、5-甲氧基吲哚、5-甲氧基色醇、5-甲氧基色胺及其可药用盐。
3.治疗或预防哺乳动物COPD的方法,该方法包括给予具有MPO抑制活性的化合物或其可药用盐。
4.权利要求3的方法,其中所述MPO抑制剂选自伯氨喹、达普宋、氨基比林、piceatannol、甲芬那酸、磺胺吡啶、磺胺、丙基硫尿嘧啶、磺胺嘧啶、磺胺异噁唑、磺胺胍、磺胺硝苯、磺胺、N-1(2-噻唑基)磺胺、双氯芬酸、吡罗昔康、香草醛、对氨基苯甲酸乙酯、3-氨基酸乙酯、对氨基苯甲酰胺、褪黑激素、6-甲氧基吲哚、吲哚、3-甲基吲哚、5-甲氧基吲哚、5-甲氧基色醇、5-甲氧基色胺及其可药用盐。
5.治疗或预防COPD的药物组合物,该药物组合物包含MPO抑制剂或其可药用盐和可药用载体或赋形剂。
6.权利要求6的组合物,其中所述MPO抑制剂选自伯氨喹、达普宋、氨基比林、piceatannol、甲芬那酸、磺胺吡啶、磺胺、丙基硫尿嘧啶、磺胺嘧啶、磺胺异噁唑、磺胺胍、磺胺硝苯、磺胺、N-1(2-噻唑基)磺胺、双氯芬酸、吡罗昔康、香草醛、对氨基苯甲酸乙酯、3-氨基酸乙酯、对氨基苯甲酰胺、褪黑激素、6-甲氧基吲哚、吲哚、3-甲基吲哚、5-甲氧基吲哚、5-甲氧基色醇、5-甲氧基色胺及其可药用盐。
7.MPO抑制剂在生产用于预防或治疗COPD药物中的应用。
8.权利要求7的应用,其中所述MPO抑制剂选自伯氨喹、达普宋、氨基比林、piceatannol、甲芬那酸、磺胺吡啶、磺胺、丙基硫尿嘧啶、磺胺嘧啶、磺胺异噁唑、磺胺胍、磺胺硝苯、磺胺、N-1(2-噻唑基)磺胺、双氯芬酸、吡罗昔康、香草醛、对氨基苯甲酸乙酯、3-氨基酸乙酯、对氨基苯甲酰胺、褪黑激素、6-甲氧基吲哚、吲哚、3-甲基吲哚、5-甲氧基吲哚、5-甲氧基色醇、5-甲氧基色胺及其可药用盐。
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US20120183524A1 (en) * | 2007-12-21 | 2012-07-19 | University Of Rochester | Molecular targets for treatment of inflammation |
CA2793170C (en) * | 2010-03-15 | 2018-04-17 | Virginia Commonwealth University | Aerosolized dapsone as a therapy for inflammation of the airway and abnormal mucociliary transport |
WO2011133581A1 (en) | 2010-04-19 | 2011-10-27 | General Atomics | Methods and compositions for assaying enzymatic activity of myeloperoxidase in blood samples |
EA027324B1 (ru) | 2011-11-11 | 2017-07-31 | Пфайзер Инк. | 2-тиопиримидиноны |
EP2682119A1 (en) * | 2012-07-03 | 2014-01-08 | Université Libre de Bruxelles | Aromatic N-heterocycle derivatives for use as medicine |
MA42035A (fr) | 2015-05-05 | 2018-03-14 | Pfizer | 2-thiopyrimidinones |
MA49618A (fr) * | 2017-07-17 | 2020-05-27 | Astrazeneca Ab | Inhibiteurs de la mpo destinés à être utilisés en médecine |
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KR0182324B1 (ko) * | 1993-11-26 | 1999-05-01 | 알렌 제이. 스피겔 | 항염증제로서의 이속사졸린 화합물 |
US5708009A (en) * | 1993-12-21 | 1998-01-13 | Eli Lilly And Company | Methods of inhibiting myeloperoxidase activity |
US5447941A (en) * | 1993-12-21 | 1995-09-05 | Eli Lilly And Company | Methods of inhibiting pulmonary hypertensive diseases with raloxifene and related benzothiophenes |
IL120268A0 (en) * | 1996-02-28 | 1997-06-10 | Pfizer | Use of (E)-1-[4'-(2-alkylaminoethioxy)phenyl]1-(3'-hydroxyphenyl)-2-phenylbut-1-enes in inhibiting pathological conditions |
WO1999059561A2 (en) * | 1998-05-18 | 1999-11-25 | Hensley, Kenneth, L. | Resveratrol inhibition of myeloperoxidase |
DZ3019A1 (fr) * | 1999-03-01 | 2005-05-20 | Smithkline Beecham Corp | Utilisation d'un inhibiteur de pde4 dans la préparation d'un médicament contre la copd. |
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2000
- 2000-05-12 GB GB0011358A patent/GB2362101A/en not_active Withdrawn
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2001
- 2001-05-08 AT AT01934724T patent/ATE273699T1/de not_active IP Right Cessation
- 2001-05-08 DE DE60105025T patent/DE60105025T2/de not_active Expired - Fee Related
- 2001-05-08 WO PCT/SE2001/001014 patent/WO2001085146A1/en active IP Right Grant
- 2001-05-08 CN CN01809152A patent/CN1427718A/zh active Pending
- 2001-05-08 CA CA002406512A patent/CA2406512A1/en not_active Abandoned
- 2001-05-08 AU AU2001260880A patent/AU2001260880A1/en not_active Abandoned
- 2001-05-08 EP EP01934724A patent/EP1294366B1/en not_active Expired - Lifetime
- 2001-05-08 JP JP2001581800A patent/JP2004509841A/ja active Pending
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103547261A (zh) * | 2010-12-23 | 2014-01-29 | 德克萨斯大学系统董事会 | 用于治疗copd的方法 |
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ATE273699T1 (de) | 2004-09-15 |
EP1294366B1 (en) | 2004-08-18 |
WO2001085146A1 (en) | 2001-11-15 |
US20040029871A1 (en) | 2004-02-12 |
EP1294366A1 (en) | 2003-03-26 |
JP2004509841A (ja) | 2004-04-02 |
CA2406512A1 (en) | 2001-11-15 |
DE60105025T2 (de) | 2005-08-18 |
DE60105025D1 (de) | 2004-09-23 |
GB2362101A (en) | 2001-11-14 |
GB0011358D0 (en) | 2000-06-28 |
AU2001260880A1 (en) | 2001-11-20 |
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