CN109280083A - 具有glp-1受体激动剂活性的glp-1多肽及其用途 - Google Patents
具有glp-1受体激动剂活性的glp-1多肽及其用途 Download PDFInfo
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- CN109280083A CN109280083A CN201710602014.4A CN201710602014A CN109280083A CN 109280083 A CN109280083 A CN 109280083A CN 201710602014 A CN201710602014 A CN 201710602014A CN 109280083 A CN109280083 A CN 109280083A
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- Prior art keywords
- glp
- polypeptide
- pharmaceutically acceptable
- amino acid
- acceptable salt
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Abstract
本申请属于医药领域。本申请涉及具有GLP‑1受体激动剂活性的GLP‑1多肽及其用途。本申请还涉及包含所述GLP‑1多肽的药物组合物。特别地，本申请涉及一种具有GLP‑1受体激动剂活性的GLP‑1多肽或其药学上可接受的盐，其特征在于所述GLP‑1多肽具有在对应于GLP‑1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变。
Description
技术领域
本申请属于医药领域。本申请涉及具有GLP-1受体激动剂活性的GLP-1多肽及其用途。本申请还涉及包含所述GLP-1多肽的药物组合物。
背景技术
胰高血糖素样肽-1(Glucagon-like peptide-1，GLP-1)是一种含有37个氨基酸的多肽。GLP-1(在本文中也称为GLP-1(1-37))的氨基酸序列为1HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG。GLP-1通过激动GLP-1受体而刺激胰岛素分泌，从而引起血糖水平下降(Bioorganic&Medicinal Chemistry Letters，2013，23，4011–4018；J.Med.Chem.，2015，58，1020-1037)。然而，GLP-1(1-37)的活性很弱。所以人们的注意力集中在GLP-1(1-37)的衍生物上，例如比GLP-1(1-37)具有更强生物学活性的GLP-1片段。GLP-1片段的例子包括GLP-1(7-37)和GLP-1(7-36)NH2。GLP-1(7-37)的序列为7HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG(SEQ ID No.1)。GLP-1(7-36)NH2的序列为7HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2(SEQ ID No.2)。
已经发现，GLP-1具有葡萄糖浓度依赖性降糖作用。在血糖水平升高的情况下，GLP-1发挥降糖作用。而在血糖水平正常时,GLP-1不会进一步降低血糖水平。因此GLP-1降低了施用降血糖药物组合物时常见的低血糖风险，具有提高的安全性。
GLP-1还具有减轻体重的功效。研究显示,在接受GLP-1治疗6周后，2型糖尿病患者的体重平均减轻了1.9kg。研究者认为,GLP-1是通过多种途径产生降低体重的作用，包括抑制胃动力、延迟胃排空等。此外，GLP-1还可作用于中枢神经系统，从而在人体中产生饱胀感和引起食欲下降。
因此，GLP-1显示出作为在糖尿病(尤其是2型糖尿病)、肥胖症和相关状况的治疗剂方面的巨大潜力。
诺和诺德公司通过在GLP-1第20位赖氨酸处连接谷氨酸、并在该谷氨酸氨基基团上进一步连接十六烷酰基(棕榈酰基)而开发了一种GLP-1类似物，其以Liraglutide(利拉鲁肽)的商品名销售。Exenatide(艾塞那肽，又称为Exendin-4)是一种天然的GLP-1类似物。Exenatide是含39个氨基酸的多肽，其是从墨西哥钝尾毒蜥(Heloderma suspectum)的唾液中分离得到的。Exenatide的序列为HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2(SEQID No.3)。
此外，已知GLP-1的8位丙氨酸(Ala8/A8)是二肽基肽酶IV(dipeptidyl peptidaseIV，DPP-IV)的靶点。通过将GLP-1或其片段的8位丙氨酸突变为甘氨酸(Gly/G)、丝氨酸(Ser/S)或苏氨酸(Thr/T)而得到的变体(例如，Gly8-GLP-1、Ser8-GLP-1或Thr8-GLP-1；参见Metabolism，1999，48，252-258，或Diabetologia，1998，41，271-278)具有提高的对DPP-IV介导降解的抗性。
发明概述
本申请提供一种具有GLP-1受体激动剂活性的GLP-1多肽或其药学上可接受的盐，其特征在于所述GLP-1多肽具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变。本申请所述GLP-1多肽或其药学上可接受盐是一种GLP-1受体激动剂，可用于治疗其中需要活化或激动GLP-1受体的疾病。
本申请还提供所述GLP-1多肽或其药学上可接受盐用于制备治疗其中需要活化或激动GLP-1受体的疾病的药物中的用途。本申请还提供用于治疗其中需要活化或激动GLP-1受体的疾病的GLP-1多肽或其药学上可接受盐。本申请还提供一种治疗其中需要活化或激动GLP-1受体的疾病的方法，包括向有需要的受试者施用治疗有效量的所述GLP-1多肽或其药学上可接受盐。
本申请还提供一种药物组合物，包含所述GLP-1多肽或其药学上可接受的盐、以及任选地药学上可接受载体。
发明详述
本申请提供一种具有GLP-1受体激动剂活性的GLP-1多肽或其药学上可接受的盐，其特征在于所述GLP-1多肽具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变。
在一种实施方式中，本申请所述GLP-1多肽包括具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变的GLP-1、具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变且具有GLP-1受体激动剂活性的GLP-1片段、或者具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变且具有GLP-1受体激动剂活性的GLP-1类似物或其片段。所述GLP-1类似物或其片段包括GLP-1的天然类似物或其片段或在其氨基酸序列中有1、2、3、4或5个氨基酸与GLP-1中相应位置上氨基酸不同的GLP-1类似物或其片段。
在一种优选的实施方式中，所述GLP-1是GLP-1(1-37)。在另一种优选的实施方式中所述GLP-1片段包括GLP-1(7-37)或GLP-1(7-36)NH2。在一种优选的实施方式中，所述GLP-1类似物或其片段包括Exenatide、Gly8-GLP-1(7-37)、Gly8-GLP-1(7-36)NH2、Ser8-GLP-1(7-37)、Ser8-GLP-1(7-36)NH2、Thr8-GLP-1(7-37)或Thr8-GLP-1(7-36)NH2。
在一种优选的实施方式中，本申请所述GLP-1多肽是Gly8-Pro13-GLP-1(7-37)、Gly8-Pro13-GLP-1(7-36)NH2、Ser8-Pro13-GLP-1(7-37)、Ser8-Pro13-GLP-1(7-36)NH2、Thr8-Pro13-GLP-1(7-37)或Thr8-Pro13-GLP-1(7-36)NH2。
Gly8-Pro13-GLP-1(7-36)NH2的序列为7HGEGTFPSDVSSYLEGQAAKEFIAWLVKGR-NH2(SEQ ID No.4)。
Gly8-Pro13-GLP-1(7-37)的序列为7HGEGTFPSDVSSYLEGQAAKEFIAWLVKGRG(SEQ IDNo.5)。
本申请所述GLP-1多肽中的氨基酸可以是取代的或未取代的。或者，本申请所述GLP-1多肽中的氨基酸可以是天然氨基酸的或非天然氨基酸。非天然氨基酸的实例包括α-甲基氨基酸(如α-甲基丙氨酸)、D-氨基酸、组氨酸样氨基酸(如2-氨基组氨酸，β-羟基-组氨酸、高组氨酸、α-氟甲基组氨酸或α-甲基组氨酸)、侧链中含有一额外亚甲基的氨基酸(“高”氨基酸)以及侧链中的羧酸官能团由磺酸基团取代了的氨基酸(如半胱氨酸)。然而，除非特别说明，本申请所述GLP-1多肽优选仅仅包含天然氨基酸。
可利用固相肽合成技术的已知方法来制备本申请中的GLP-1多肽或其药学上可接受盐(参见CN101337989B、CN1786031B)。肽合成仪可从如Applied Biosystems商业购得。用于固相合成的试剂可从如Midwest Biotech或GL Biochem商业购得。利用固相肽合成仪，可按照生产说明书来阻断干扰基团、保护要进行反应的氨基酸、偶合、去偶合及对未反应的氨基酸进行加帽。也可以利用基因工程的方法来制备本申请中的GLP-1多肽或其药学上可接受盐。
本申请所述GLP-1多肽、GLP-1、GLP-1片段、GLP-1类似物或其片段中的氨基酸的编号是按照本领域广泛接受的方式确定的(比如，按照GLP-1氨基酸序列的编号确定)。例如，按照本领域中的习惯，GLP-1(7-37)的氨基末端定为第7位，而羧基末端定为第37位。对多肽中的其他氨基酸依次进行编号。在没有特别指出的情况下，C-末端是未取代的羧基形式。
定义
在一些实施方式中，GLP-1是指具有37个氨基酸的GLP-1(1-37)。在还有一些实施方式中，GLP-1是指GLP-1、GLP-1片段、GLP-1类似物或其片段。本领域技术人员能够根据上下文确定术语GLP-1的含义。
“GLP-1多肽”包括具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变(即T13P突变)的GLP-1、具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变且具有GLP-1受体激动剂活性的GLP-1片段、或者具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变且具有GLP-1受体激动剂活性的GLP-1类似物或其片段。
“GLP-1”是GLP-1(1-37)。
“GLP-1片段”是具有GLP-1受体激动剂活性的GLP-1的片段(例如GLP-1(7-37)、GLP-1(7-36)NH2)。GLP-1片段包括在GLP-1或其片段(例如，GLP-1(1-37)、GLP-1(7-37)、GLP-1(7-36)NH2)的N-末端或C-末端截掉一或多个氨基酸后得到的多肽。例如，GLP-1(9-36)表示在GLP-1(7-37)的N-末端截掉2个氨基酸和在C-末端截掉1个氨基酸后得到的片段。而且，该片段中的氨基酸是用与GLP-1(7-37)中对应氨基酸编号相同的编号来表示的。例如，GLP-1(9-36)中的N-末端谷氨酸在第9位；第12位是苯丙氨酸，而第22位是甘氨酸，这与GLP-1(7-37)相同。优选地，所述GLP-1片段中的氨基酸是用与GLP-1中对应氨基酸编号相同的编号来表示的。
“GLP-1类似物或其片段”是指与GLP-1或其片段(例如，GLP-1(1-37)、GLP-1(7-37)、GLP-1(7-36)NH2)具有同源性并且也具有GLP-1受体激动剂活性的多肽。所述GLP-1类似物或其片段包括GLP-1的天然类似物或其片段或在其氨基酸序列中有1、2、3、4或5个氨基酸与GLP-1中相应位置上氨基酸不同的GLP-1类似物或其片段。在一种优选的实施方式中，所述GLP-1类似物或其片段包括Exenatide、Gly8-GLP-1(1-37)、Gly8-GLP-1(7-36)NH2、Ser8-GLP-1(7-37)、Ser8-GLP-1(7-36)NH2、Thr8-GLP-1(1-37)或Thr8-GLP-1(7-36)NH2。优选地，所述GLP-1类似物或其片段中的氨基酸是用与GLP-1或其片段(例如，GLP-1(1-37)、GLP-1(7-37)、GLP-1(7-36)NH2)中对应氨基酸编号相同的编号来表示的。
在一种优选的实施方式中，本申请所述GLP-1多肽是Gly8-Pro13-GLP-1(7-37)、Gly8-Pro13-GLP-1(7-36)NH2、Ser8-Pro13-GLP-1(7-37)、Ser8-Pro13-GLP-1(7-36)NH2、Thr8-Pro13-GLP-1(7-37)或Thr8-Pro13-GLP-1(7-36)NH2。
在一种实施方式中，本申请所述GLP-1多肽的N-末端是未取代的。在另一种实施方式中，本申请所述GLP-1多肽的N-末端被烷基化或酰基化(优选使用C1-C20烷基或酰基基团进行烷基化或酰基化)。在一种实施方式中，本申请所述GLP-1多肽的C末端是未取代的。在另一种实施方式中，本申请所述GLP-1多肽的C末端被-NH2、-NHR或-NRR'基团酰胺化或被(C1-C20)烷基基团酯化。
由于本申请所述GLP-1多肽在其氨基酸序列中可含有酸性、碱性官能团或两者兼具。因此，本申请所述GLP-1多肽能够与多种无机碱、无机酸和有机酸进行反应形成盐。通常用于形成酸性盐的酸是无机酸，如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等，和有机酸如对甲苯磺酸、甲烷磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠椽酸、苯甲酸、乙酸等。这些盐的实例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、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、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁烯-1,4-二酸盐、己烯-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、苯二甲酸盐、酒石酸盐、甲烷磺酸盐、丙烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。
碱加成盐可由无机碱生成，例如铵，碱金属或碱土金属的氢氧化物，碳酸盐，重碳酸盐等等。下述碱性物质常用来生成碱性盐，如氢氧化钠，氢氧化钾，氢氧化铵，碳酸钾等等。优选地，本申请所述GLP-1多肽的盐是药学上可接受的盐。
本申请所述需要活化或激动GLP-1受体的疾病包括选自以下的一种或多种疾病：糖尿病(例如1型糖尿病或2型糖尿病)、肥胖症、卒中、手术后分解代谢改变、或肠易激综合征。
本申请还提供所述GLP-1多肽或其药学上可接受盐用于制备治疗其中需要活化或激动GLP-1受体的疾病的药物中的用途。本申请还提供用于治疗其中需要活化或激动GLP-1受体的疾病的GLP-1多肽或其药学上可接受盐。本申请还提供一种治疗其中需要活化或激动GLP-1受体的疾病的方法，包括向有需要的受试者施用治疗有效量的所述GLP-1多肽或其药学上可接受盐。
本申请还提供一种药物组合物，包含所述GLP-1多肽或其药学上可接受的盐、以及任选地药学上可接受载体。本申请所述药物组合物可以是片剂、胶囊剂、颗粒剂、糖浆剂、悬浮液、溶液、分散剂、用于口服或非口服给药的缓释制剂、静脉注射制剂、皮下注射制剂、吸入制剂、透皮制剂、直肠或阴道栓剂。
本申请所述药学上可接受载体是指本领域技术人员熟知的药学上可接受载体，本申请的药学上可接受载体包括但不限于：填充剂、润湿剂、黏合剂、崩解剂、润滑剂、粘合剂、助流剂、掩味剂、表面活性剂、防腐剂等。填充剂包括但不限于乳糖、微晶纤维素、淀粉、糖粉、糊精、甘露醇、硫酸钙等。润湿剂与黏合剂包括但不限于羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、明胶、蔗糖、聚乙烯吡咯烷酮等。崩解剂包括但不限于羧甲基淀粉钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、低取代羟丙基纤维素等。润滑剂包括但不限于硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇、月桂醇硫酸镁等。粘合剂包括但不限于阿拉伯胶、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、葡萄糖结合剂、糊精、右旋糖、乙基纤维素、明胶、液体葡萄糖、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸铝镁、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚乙烯吡咯烷酮、预明胶化淀粉、藻酸钠、山梨醇、淀粉、糖浆和黄蓍胶。助流剂包括但不限于胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉。掩味剂包括但不限于阿斯巴坦、甜菊苷、果糖、葡萄糖、糖浆、蜂蜜、木糖醇、甘露醇、乳糖、山梨醇、麦芽糖醇、甘草甜素。表面活性剂包括但不限于吐温-80、泊洛沙姆。防腐剂包括但不限于尼泊金酯、苯甲酸钠、山梨酸钾等。
制备各种含有各种比例活性成分的药物组合物的方法是已知的，或根据本申请的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述。制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。以已知的方法制造本申请所述药物组合物，包括常规的混合、溶解或冻干方法。
在本申请所述药物组合物中，活性成分的比例可以变化，可占给定的单位剂型重量的大约0.01％至大约99％。在这种治疗有用的药物组合物制剂中，活性成分的量使得能够获得有效剂量水平。
本申请所述的片剂、胶囊剂等可以包含：粘合剂，如黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂，如磷酸氢二钙；崩解剂，如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂，如硬脂酸镁；和甜味剂，如蔗糖、果糖、乳糖或阿司帕坦；或调味剂，如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时，除了上面类型的材料，它还可以包含液体载体，如植物油或聚乙二醇。各种其他材料可以存在，作为包衣，或以其他方式改变固体单位剂型的物理形式。例如，片剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆可以包含活性成分，蔗糖或果糖作为甜味剂，对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂，染料和调味剂(如樱桃香料或桔子香料)。当然，用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量为无毒。此外，活性成分可以掺入缓释制剂和缓释装置中。
活性成分也可以通过输注或注射到静脉内或腹膜内施用。可以制备活性成分或其盐的水溶液，任选可混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下，这些制剂包含防腐剂以防止微生物生长。
适于注射或输注的药物组合物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下，最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质，包括，例如水、乙醇、多元醇(例如，甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性，例如，通过脂质体的形成，通过在分散剂的情况下维持所需的粒子大小，或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下，优选包括等渗剂，如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如，单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。
通过将合适的溶剂中的需要量的活性成分与需要的上面列举的各种其他成分结合，然后进行过滤灭菌，制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下，优选的制备方法是真空干燥和冷冻干燥技术，这会产生活性成分加上任何另外需要的无菌过滤溶液中存在的成分的粉末。
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物，本申请的药物组合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等，直接用于使用者的皮肤上。
活性成分的治疗有效量，不仅取决于选择的特定的盐，而且取决于施药方式、待治疗的疾病的性质和患者的年龄和状态，最终取决于在场医师或临床医生的决定。
上述制剂可以以单位剂型存在，该单位剂型是含有单位剂量的物理分散单元，适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂。根据所涉及的具体治疗，活性成分的单位剂量的量可以在大约0.01到大约1000毫克或更多之间进行变化或调整。
本申请使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。
本申请所述GLP-1多肽或其药学上可接受的盐还可以一种或多种用于治疗糖尿病的额外治疗剂联合施用。所述额外治疗剂包括，但不限于，磺脲类药物(例如格列苯脲、格列齐特、格列吡嗪、格列喹酮、格列美脲等)、双胍类药物(例如二甲双胍)、α-葡萄糖苷酶抑制剂(阿卡波糖、伏格列波糖等)、噻唑烷二酮类药物(例如罗格列酮)。
具体实施方式
下面，本申请将通过实施例展示本申请的有益效果。本领域技术人员会知道，这些实施例是示例性的，而不是限制性的。这些实施例不会以任何方式限制本申请的范围。下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实施例1：制备Gly8-Pro13-GLP-1(7-36)NH2
Gly8-Pro13-GLP-1(7-36)NH2的一级结构为：His-Gly-Glu-Gly-Thr-Phe-Pro-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH2。本实施例采用MBHA Rink amide树脂(购自GL Biochem)，以从Arg至His的顺序合成Gly8-Pro13-GLP-1(7-36)NH2。
1.1)第一个氨基酸Fmoc-Arg(Pbf)-OH与MBHA Rink amide树脂的偶联：
将100克MBHA Rink amide树脂加入2L反应瓶中，接着向反应瓶加入1L的25％六氢吡啶/DMF溶液。30分钟后，通过负压抽吸装置移除所述六氢吡啶/DMF溶液。然后，向所述反应瓶中加入32.7克Fmoc-Arg(Pbf)-OH、6.8克1-羟基苯并三唑(HOBt)、7.84毫升N,N-二异丙基碳二亚胺(DIC)和500毫升DMF。持续反应120分钟。通过过滤收集树脂。依次用异丙醇、DMF、异丙醇、DMF、异丙醇、乙醚洗涤所收集的树脂。将洗涤的树脂干燥至恒重。
1.2)第二个氨基酸的偶联：
1.2.1)脱保护：将带有第一个氨基酸并干燥过的树脂加入2L反应瓶中。向该反应瓶中加入1L的DMF，以使所述树脂充分溶胀。经负压抽吸装置将所述DMF移入废液瓶。向反应瓶中加入1L的25％六氢吡啶/DMF溶液，然后将反应瓶放置在摇床上(摇床速度：120转/分钟)反应30分钟。经负压抽吸装置将液体移入废液瓶。用DMF、异丙醇、DMF、异丙醇、DMF依次洗涤树脂，其中每次洗涤后均经负压抽吸装置将洗涤液体移入废液瓶。
1.2.2)偶联反应：将53.5克Fmoc-Gly-OH、28.0毫升DIC和24.3克HOBt加入锥形瓶中，然后加入500毫升DMF使之溶解，以得到溶液。将所述锥形瓶放置在摇床上活化10分钟(摇床速度：120转/分钟)，得到活化的溶液。将所述活化的溶液加入到含有步骤1.2.1)所得树脂的反应瓶中。然后将反应瓶放置在摇床中(摇床速度：120转/分钟)反应120分钟。经负压抽吸装置将液体移入废液瓶。用DMF、异丙醇、DMF、异丙醇依次洗涤树脂，其中每次洗涤后均经负压抽吸装置将洗涤液体移入废液瓶。将洗涤的树脂干燥至恒重。
1.3)第三至三十个氨基酸的偶联：
依次使用84.3克Fmoc-Lys(Boc)-OH、61.1克Fmoc-Val-OH、63.6克Fmoc-Leu-OH、94.8克Fmoc-Trp(BOC)-OH、56.0克Fmoc-Ala-OH、63.6克Fmoc-Ile-OH、69.7克Fmoc-Phe-OH、76.6克Fmoc-Glu(OtBu)-OH、84.3克Fmoc-Lys(Boc)-OH、56.0克Fmoc-Ala-OH、56.0克Fmoc-Ala-OH、109.9克Fmoc-Gln(Trt)-OH、53.5克Fmoc-Gly-OH、76.6克Fmoc-Glu(OtBu)-OH、63.6克Fmoc-Leu-OH、82.7克Fmoc-Tyr(tBu)-OH、69.0克Fmoc-Ser(tBu)-OH、69.0克Fmoc-Ser(tBu)-OH、61.1克Fmoc-Val-OH、74.07克Fmoc-Asp(OtBu)-OH、69.0克Fmoc-Ser(tBu)-OH、60.7克Fmoc-Pro-OH、69.7克Fmoc-Phe-OH、71.5克Fmoc-Thr(tBu)-OH、53.5克Fmoc-Gly-OH、109.9克Fmoc-Glu(OtBu)-OH、53.5克Fmoc-Gly-OH、111.5可Fmoc-His(Trt)-OH作为反应试剂重复步骤1.2)，得到干燥的His(Trt)-Gly-Glu(OtBu)-Gly-Thr(tBu)-Phe-Pro-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly-Gln(Trt)-Ala-Ala-Lys(Boc)-Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Lys(Boc)-Gly-Arg(pbf)-树脂。
1.4)将干燥的His(Trt)-Gly-Glu(OtBu)-Gly-Thr(tBu)-Phe-Pro-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly-Gln(Trt)-Ala-Ala-Lys(Boc)-Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Lys(Boc)-Gly-Arg(pbf)-树脂加入至2L的圆底烧瓶中。向所述烧瓶中加入1L的TFA/H2O/EDT(V/V/V＝95:2.5:2.5)。将所述烧瓶放置摇床上反应2小时(转速120转/分钟)。过滤反应液体，得到滤液。将所述滤液分批加入到3L的无水乙醚中，产生白色沉淀。通过过滤收集沉淀物并称重，得到220克的Gly8-Pro13-GLP-1(7-36)NH2粗品。通过HPLC纯化所述粗品，得到纯化的Gly8-Pro13-GLP-1(7-36)NH2：MSm/z＝3,280.6(单电荷)；1640.8(双电荷)；1094.2(三电荷)。
实施例2：Gly8-Pro13-GLP-1(7-36)NH2、Exenatide和Liraglutide皮下给药的药效研究
1)2型糖尿病实验动物模型
将约200克雄性Wistar大鼠禁食过夜，其间可自由饮水。向所述大鼠以45mg/Kg的量经腹腔注射(ip)一次性施用链脲佐菌素(STZ)。随后正常饲喂所述大鼠，并检测大鼠空腹血糖。大鼠空腹血糖持续稳定地高于20mM，则提示造模成功。
2)实验方法
将48只大鼠随机分成6组，每组8只。在实验开始时(0小时)，所述大鼠(STZ大鼠)血糖浓度为26.1±1.7mM(n＝48)。在第0小时，向所述STZ大鼠皮下注射不同剂量的待测药物。在第3，6和9小时，从所述大鼠尾部静脉采集血液样品。检测所述血液样品以得到所述大鼠的血糖浓度。
实验结果如下表所示
表1
以上数据表明：Gly8-Pro13-GLP-1(7-36)NH2的降血糖效果显著优于Liraglutide(P<0.01)。
Gly8-Pro13-GLP-1(7-36)NH2的降血糖效果与Exenatide相似，无显著性差异。但是，与Exenatide相比，预期Gly8-Pro13-GLP-1(7-36)NH2引起较少的异常免疫反应。
Claims (13)
1.一种具有GLP-1受体激动剂活性的GLP-1多肽或其药学上可接受的盐，其特征在于所述GLP-1多肽具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变。
2.如权利要求1所述的GLP-1多肽或其药学上可接受的盐，其中所述GLP-1多肽包括具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变的GLP-1、具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变且具有GLP-1受体激动剂活性的GLP-1片段、或者具有在对应于GLP-1氨基酸序列第13位位置上的苏氨酸至脯氨酸的突变且具有GLP-1受体激动剂活性的GLP-1类似物或其片段。
3.如权利要求2所述的GLP-1多肽或其药学上可接受的盐，其中所述GLP-1是GLP-1(1-37)。
4.如权利要求2所述的GLP-1多肽或其药学上可接受的盐，其中所述GLP-1片段包括GLP-1(7-37)或GLP-1(7-36)NH2。
5.如权利要求2所述的GLP-1多肽或其药学上可接受的盐，其中所述GLP-1类似物或其片段包括GLP-1的天然类似物或其片段或在其氨基酸序列中有1、2、3、4或5个氨基酸与GLP-1中相应位置上氨基酸不同的GLP-1类似物或其片段。
6.如权利要求5所述的GLP-1多肽或其药学上可接受的盐，其中所述GLP-1类似物或其片段包括Exenatide、Gly8-GLP-1(1-37)、Gly8-GLP-1(7-36)NH2、Ser8-GLP-1(7-37)、Ser8-GLP-1(7-36)NH2、Thr8-GLP-1(1-37)或Thr8-GLP-1(7-36)NH2。
7.如权利要求1-6任一项所述的GLP-1多肽或其药学上可接受的盐，其中所述GLP-1多肽是Gly8-Pro13-GLP-1(7-37)、Gly8-Pro13-GLP-1(7-36)NH2、Ser8-Pro13-GLP-1(7-37)、Ser8-Pro13-GLP-1(7-36)NH2、Thr8-Pro13-GLP-1(7-37)或Thr8-Pro13-GLP-1(7-36)NH2。
8.一种药物组合物，包含如权利要求1-7任一项所述的GLP-1多肽或其药学上可接受的盐、以及任选的药学上可接受载体。
9.如权利要求8所述的药物组合物，其中所述药物组合物是片剂、胶囊剂、颗粒剂、糖浆剂、悬浮液、溶液、分散剂、用于口服或非口服给药的缓释制剂、静脉注射制剂、皮下注射制剂、吸入制剂、透皮制剂、直肠或阴道栓剂。
10.如权利要求1-7任一项所述的GLP-1多肽或其药学上可接受的盐用于制备治疗其中需要活化或激动GLP-1受体的疾病的药物中的用途。
11.用于治疗其中需要活化或激动GLP-1受体的疾病的如权利要求1-7任一项所述的GLP-1多肽或其药学上可接受的盐。
12.一种治疗其中需要活化或激动GLP-1受体的疾病的方法，包括向有需要的受试者施用治疗有效量的如权利要求1-7任一项所述的GLP-1多肽或其药学上可接受的盐。
13.如权利要求10-12所述的用途、GLP-1多肽或其药学上可接受的盐或方法，其中所述需要活化或激动GLP-1受体的疾病包括：糖尿病、肥胖症、卒中、手术后分解代谢改变、或肠易激综合征。
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