CN1381271A - 促胰岛素分泌肽Exendin4类似物及其盐的新用途 - Google Patents
促胰岛素分泌肽Exendin4类似物及其盐的新用途 Download PDFInfo
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- CN1381271A CN1381271A CN 02111564 CN02111564A CN1381271A CN 1381271 A CN1381271 A CN 1381271A CN 02111564 CN02111564 CN 02111564 CN 02111564 A CN02111564 A CN 02111564A CN 1381271 A CN1381271 A CN 1381271A
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- exendin
- lys
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- salt
- diabetes
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Abstract
本发明公开了一种促胰岛素分泌肽Exendin4类似物及其盐的新用途,具体来说,公开了促胰岛素分泌肽Exendin4类似物及其盐在制备治疗II型糖尿病的药物中的应用。本发明将Exendin4类似物应用于II型糖尿病治疗,能够降低治疗成本,改善治疗效果,显著提高糖尿病患者的生活质量。
Description
技术领域
本发明涉及促胰岛素分泌肽Exendin 4类似物及其盐的新用途，具体的说，涉及该促胰岛素分泌肽Exendin 4类似物及其盐在制备治疗II型糖尿病的药物中的应用。
背景技术
糖尿病分为二种类型：I型和II型。I型糖尿病称为胰岛素依赖性糖尿病(IDDM)，这类糖尿病患者胰脏丧失合成胰岛素的能力，需要注射外源胰岛素，患者多为青少年。II型糖尿病称为非胰岛素依赖性糖尿病(NIDDM)，患者以成年人为主。糖尿病患者中II型占90％以上，其余为I型，各国情况都相似。
糖尿病是世界性疾病。1998年统计结果，美国的糖尿病患者约为II型1200万，I型100万。1999年，日本糖尿病患者690万(I型约占10％)，中国糖尿病患者约为人口的3.6％，共4000万，90％以上为II型。印度糖尿病患者多于我国。糖尿病患者需终生用药，因此开发高效低价的II型糖尿病新药具有重大的社会保健意义和经济意义。
II型糖尿病患者是一个病因复杂的群体，其主要特点是胰脏具有合成胰岛素能力，但胰岛素分泌量不足，餐后胰岛素分泌滞后。
一般而言，可以通过使用胰岛素、口服药物以及饮食控制等手段来治疗或控制糖尿病。根据1988年日本对糖尿病临床治疗的调查，饮食控制占35％，注射胰岛素占25％，口服药物占40％。
对NIDDM病人，促进胰脏β-细胞分泌胰岛素进而控制血糖是II型糖尿病治疗药物的一个重要目标，磺酰脲类药物提供了促进胰岛素分泌治疗NIDDM的途径，但其促进胰脏分泌胰岛素作用并不依赖血糖浓度的高低，药物进入体内后不断地刺激胰脏分泌胰岛素，容易产生低血糖，对糖基血红蛋白HbA1c含量无降低作用。此类药物还有诸多副作用，而且每年都有相当数量的糖尿病患者应用此类药物不再奏效。
近年来对促胰岛素分泌肽GLP-1和Exendin 4的研究进展很快，应用于治疗II型糖尿病效果很好。GLP-1是人肠道中分离纯化得到的多肽，Exendin4从墨西哥巨蜥蜴的毒液中分离得到(1996年Jean-Pierre Ranfman首先在《Regulatory Peptides》杂志上报道发现Exendin 4)。两者在很低浓度下即可促进胰脏合成和分泌胰岛素(Diabetologia，1996年，39卷，1546-1553页；Diabetologia，1999年，42卷，45-50页)，从而能帮助糖尿病人控制血糖。
研究表明，缺乏C肽与糖尿病的并发症存在密切联系，这些并发症包括肾功能衰竭，神经功能失控以及视网膜病变。胰岛细胞在分泌胰岛素的同时，会相应分泌C肽。因此，GLP-1和Exendin 4给药能同时促进胰岛素和C肽的分泌，这有助于减轻上述并发症的症状，控制糖尿病的病情。
以上这些研究表明促胰岛素分泌肽在II型糖尿病治疗方面良好的应用前景。
美国专利USP 05424286公开了Exendin 4与GLP-1促胰岛素分泌的对比实验。与GLP-1相比，产生促胰岛素分泌作用所需的Exendin 4浓度更低，而且Exendin 4在人体内的半衰期更长。这些研究表明，Exendin 4可能成为一种较为理想的II型糖尿病治疗药物。
一般可采用化学合成和基因工程技术两种方法生产多肽。但生产Exendin4的成本很高，这成为其进入药品市场的障碍。
通过改变肽链中的少数若干个氨基酸可得到Exendin 4的类似物，这些类似物有可能具有与Exendin 4相似的促胰岛素分泌作用，同时又可以大规模低成本地进行生产，从而有可能为糖尿病患者大量提供价格很低的促胰岛素分泌肽药品。
发明内容
本发明提供了三种促胰岛素分泌肽Exendin 4类似物及其盐在制备治疗II型糖尿病的药物中的应用。
本发明提供的促胰岛素分泌肽Exendin 4类似物的分子结构如式1和式2所示：
10
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-
20 30Glu-Glu-Glu-Ala-Val-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-
40Pro-Ser-Ser-Gly-A1a-Pro-Pro-Pro-Ser-Arg-OH (式1)
10
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Leu(Ile)-
20 30Glu-Glu-Glu-Ala-Val-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-
40Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-OH (式2)
式2中第14个氨基酸为Leu或Ile。
上述三种促胰岛素分泌肽的结构及制备方法均已由本发明的申请人在其申请号为01112856.9，申请日为2001年5月10日的发明专利申请说明书中公开。
天然的Exendin 4是一个由39个氨基酸构成的多肽，化学结构式如式3所示：
10
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-
20 30Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-
39Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 (式3)
式1的Lys20，Arg40与Exendin 4相区别，简写为Exendin 4(Lys20，Arg40)。
式2的Leu14(Ile14)，Lys20，Arg40与Exendin 4相区别，简写为Exendin4(Leu14/Ile14，Lys20，Arg40)。
本发明提供的Exendin 4类似物是两性化合物，可与酸性或碱性物质反应形成盐。通常采用的形成酸加成盐的酸为：盐酸，氢溴酸，氢碘酸，硫酸，磷酸，对-甲苯磺酸，甲磺酸，草酸，对溴苯基磺酸，碳酸，琥珀酸，柠檬酸，苯甲酸，乙酸等。这类盐的例子包括硫酸盐，焦硫酸盐，硫酸氢盐，亚硫酸盐，亚硫酸氢盐，磷酸盐，磷酸氢盐，磷酸二氢盐，偏磷酸盐，焦磷酸盐，盐酸盐，溴化物，碘化物，乙酸盐，丙酸盐，癸酸盐，辛酸盐，丙烯酸盐，甲酸盐，异丁酸盐，己酸盐，庚酸盐，丙炔酸盐，草酸盐，丙二酸盐，丁二酸盐，辛二酸盐，癸二酸盐，富马酸盐，马来酸盐，丁炔-1，4-二酸盐，己炔-1，6-二酸盐，苯甲酸盐，氯苯甲酸盐，甲基苯甲酸盐，二硝基苯甲酸盐，羟基苯甲酸盐，甲氧基苯甲酸盐，苯乙酸盐，苯丙酸盐，苯丁酸盐，柠檬酸盐，乳酸盐，γ-羟基丁酸盐，甘醇酸盐，酒石酸盐，甲磺酸盐，丙磺酸盐，萘-1-磺酸盐，萘-2-磺酸盐，扁桃酸盐等，优选的酸加成盐是Exendin 4类似物与无机酸如盐酸，氢溴酸，尤其是盐酸形成的盐。
碱性物质也可以与Exendin 4反应形成盐，这些碱性物质包括铵，碱金属或碱土金属的氢氧化物，以及碳酸盐，碳酸氢盐等。典型的有氢氧化钠，氢氧化钾，氢氧化铵，碳酸钾等。
本发明的此一用途，可以通过提供包含该活性成分的各种制剂来实现，这些制剂包括有：注射剂，口含片，舌下贴片，口颊膜贴片，肠溶制剂，鼻喷剂，肺部吸入剂，直肠栓剂，皮下包埋剂。
用本发明提供的糖尿病治疗方法，将低价高效的促胰岛素分泌肽应用于II型糖尿病治疗，能够降低治疗成本，改善治疗效果，显著提高糖尿病患者的生活质量。
附图说明
图1为Exendin 4(Iys20，Arg40)和Exendin 4(Leu14，Lys20，Arg40)的降血糖作用实验结果示意图。
图2为Exendin 4(Lys20，Arg40)的促胰岛素分泌作用实验结果示意图。
图3为Exendin 4(Lys20，Arg40)的促C肽分泌作用实验结果示意图。
具体实施方式
用动物实验可以证明本发明提供的Exendin 4类似物的促胰岛素分泌、促C肽分泌以及降血糖的生理作用。
实施例1 Exendin 4(Lys20，Arg40)和Exendin 4(Leu14，Lys20，Arg40)对NOD小鼠的降血糖作用
实验材料与方法：
NOD小鼠禁食过夜(中国科学院上海动物中心提供)
0.9％NaCl溶液，Exendin 4(Lys20，Arg40)，Exendin 4(Leu14，Lys20，Arg40)
血糖测定试剂盒(中国卫生部上海生物制品所出品)
NOD小鼠禁食过夜，分为三组。第一组腹腔注射200微升40％葡萄糖和1微克Exendin 4(Lys20，Arg40)，第二组腹腔注射200微升40％葡萄糖和2微克Exendin 4(Leu14，Lys20，Arg40)，第三组为对照组，只注射葡萄糖。立刻用刻度毛细管(注射前以肝素处理)从眼窦取血20微升，置入300微升生理盐水中混匀，3000转/分离心除去红血球，血清用于血糖浓度测定。分别于30，60，120分钟按同样操作取血，分离血清。三组血清均按照试剂盒所述方法测定血糖浓度，以检验GLP-1(7-36)的降血糖作用。
结果如图1所示。
对照组血糖浓度大幅度升高后，逐渐回落到正常水平；而给药组血糖浓度未出现显著升高，一直保持在正常水平附近。这是由于给药后促进了胰岛素分泌，从而避免了血糖浓度的大幅波动。由此可证明Exendin 4(Lys20，Arg40)和Exendin 4(Leu14，Lys20，Arg40)的降血糖作用。
实施例2 Exendin 4(Lys20，Arg40)的促胰岛素分泌作用
实验材料与方法：
NOD小鼠(中国科学院上海动物中心提供)
40％葡萄糖溶液，0.9％NaCl溶液，Exendin 4(Lys20，Arg40)
放射免疫胰岛素测定试剂盒(中国卫生部上海生物制品所出品)
NOD小鼠分成两组。首先用刻度毛细管(先以1mg/mL肝素润洗毛细管内壁并晾干)从眼窦取血50微升，然后两组小鼠分别腹腔注射5微克Exendin 4(Lys20，Arg40)和200微升生理盐水，并记此时为零时刻。然后分别于5，10，20，30分钟按同样操作取血。取血后各血样立刻加入盛有50微升生理盐水的离心管中，混匀，3000转/分离心除去红血球，按放射免疫试剂盒使用方法测定血清中胰岛素浓度，以检验Exendin 4(Lys20，Arg40)的促胰岛素分泌作用。
实验结果如图2所示。该结果表明，腹腔注射Exendin 4(Lys20，Arg40)能显著促进胰岛素的分泌。
实施例3 Exendin 4(Lys20，Arg40)的促C肽分泌作用
实验材料与方法：
健康C57/BL小鼠(中国科学院上海动物中心提供)
40％葡萄糖溶液，0.9％NaCl溶液，Exendin 4(Lys20，Arg40)
放射免疫胰岛素测定试剂盒(中国卫生部上海生物制品所出品)
放射免疫C-肽测定试剂盒(中国卫生部上海生物制品所出品)
健康C57/BL小鼠分成两组。首先用刻度毛细管(先以1mg/mL肝素润洗毛细管内壁并晾干)从眼窦取血50微升，然后两组小鼠分别腹腔注射5微克Exendin 4(Lys20，Arg40)和200微升生理盐水，并记此时为零时刻。然后分别于5，10，20，30分钟按同样操作取血。取血后各血样立刻加入盛有50微升生理盐水的离心管中，混匀，3000转/分离心除去红血球，按放射免疫试剂盒使用方法测定血清中C肽浓度，以检验Exendin 4(Lys20，Arg40)的促C肽分泌作用。
实验结果如图3所示。该结果表明，腹腔注射Exendin 4(Lys20，Arg40)能显著促进C肽的分泌。
Claims (2)
1.促胰岛素分泌肽Exendin 4类似物在制备治疗II型糖尿病的药物中的应用。
2.根据权利要求1所述的促胰岛素分泌肽Exendin 4类似物的盐在制备治疗II型糖尿病的药物中的应用。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008091177A1 (en) | 2007-01-18 | 2008-07-31 | Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva' | Exenatide and dalargin-based medicinal preparation for treating pancreatic diabetes |
| CN102532301A (zh) * | 2010-12-31 | 2012-07-04 | 上海医药工业研究院 | 一类新型的Exendin-4类似物及其制备方法 |
| CN104998251A (zh) * | 2015-07-08 | 2015-10-28 | 哈尔滨吉象隆生物技术有限公司 | 用于口服肠溶制剂制备的具有促肠吸收作用的利拉鲁肽盐 |
| CN105079793A (zh) * | 2015-07-18 | 2015-11-25 | 哈尔滨吉象隆生物技术有限公司 | 一种可用于口服的利拉鲁肽与盐酸二甲双胍复方制剂 |
-
2002
- 2002-04-29 CN CN 02111564 patent/CN1381271A/zh active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008091177A1 (en) | 2007-01-18 | 2008-07-31 | Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva' | Exenatide and dalargin-based medicinal preparation for treating pancreatic diabetes |
| CN102532301A (zh) * | 2010-12-31 | 2012-07-04 | 上海医药工业研究院 | 一类新型的Exendin-4类似物及其制备方法 |
| CN102532301B (zh) * | 2010-12-31 | 2014-09-03 | 上海医药工业研究院 | 一类新型的Exendin-4类似物及其制备方法 |
| CN104998251A (zh) * | 2015-07-08 | 2015-10-28 | 哈尔滨吉象隆生物技术有限公司 | 用于口服肠溶制剂制备的具有促肠吸收作用的利拉鲁肽盐 |
| CN105079793A (zh) * | 2015-07-18 | 2015-11-25 | 哈尔滨吉象隆生物技术有限公司 | 一种可用于口服的利拉鲁肽与盐酸二甲双胍复方制剂 |
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