CN109248323B - 酰化的glp-1衍生物 - Google Patents
酰化的glp-1衍生物 Download PDFInfo
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- CN109248323B CN109248323B CN201810177659.2A CN201810177659A CN109248323B CN 109248323 B CN109248323 B CN 109248323B CN 201810177659 A CN201810177659 A CN 201810177659A CN 109248323 B CN109248323 B CN 109248323B
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- glp
- hooc
- pharmaceutically acceptable
- peptide conjugate
- islet
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Abstract
本发明提供了GLP‑1(7‑37)多肽衍生物的脂肪酸修饰的缀合物。另外,本发明还提供了该肽缀合物的制备方法、含该肽缀合物的药物以及在制备药物中的用途和中间体等。
Description
技术领域
本发明属于多肽技术领域,具体而言,本发明涉及GLP-1(7-37)多肽衍生物的脂肪酸修饰的缀合物。另外,本发明还涉及该肽缀合物的制备方法、含该肽缀合物的药物以及在制备药物中的用途和中间体等。
背景技术
糖尿病是一种由遗传和环境等多种因素引起的糖代谢紊乱疾病,现已成为继肿瘤、心脑血管疾病之后威胁人类健康和生命安全的第三位重大疾病。糖尿病本身不一定造成危害,但长期血糖增高,大血管、微血管受损并危及心、脑、肾、周围神经、眼睛、足等,据世界卫生组织统计,糖尿病并发症高达100多种,是目前已知并发症最多的一种疾病。因糖尿病死亡者有一半以上是心脑血管所致,10%是肾病变所致。因糖尿病截肢是非糖尿病的10~20倍。为此治疗糖尿病进而预防其并发症是至关重要的社会问题。
糖尿病由于患病机理不同可分为几种类型。其中绝大部分属于二型糖尿病(约90%),主要是因体重过重和缺乏身体活动所致。II型糖尿病患者多存在胰岛素抵抗和胰岛素分泌不足两方面异常,在发病的中晚期往往出现胰岛β细胞凋亡。目前,临床使用的口服降糖药的作用机理多为增强胰岛素敏感性,或促进胰岛素分泌以稳定血糖,均无法解决β细胞凋亡这一难题。而胰高血糖素样肽-1(GLP-1)及其类似物药物由于具有减缓β细胞凋亡,增进其再生,促使胰岛β细胞分化并增殖的作用,使其成为治疗II型糖尿病的研究重点。
GLP-1是由回肠和结肠的L-细胞分泌的肠降血糖素。GLP-1的作用是以葡萄糖依赖的方式增加胰岛素释放从而防止低血糖症发生。由于这种性质,其作用于2型糖尿病的潜在治疗而受到关注。然而,使用GLP-1作为治疗药剂的主要障碍是其在血浆中小于4分钟的极其短的半衰期。
作为稳定肽并抑制它通过蛋白水解酶降解的方法,已经进行了一些实验来修饰对该蛋白水解酶敏感的特定氨基酸序列。由于GLP-1(7-37或7-36酰胺)通过二肽基肽酶IV(DPP IV)在第8位氨基酸(Ala)和第9位氨基酸(Asp)之间进行剪切而损失具有生物活性的GLP-1的药物浓度,因此具有减少血液中葡萄糖浓度以治疗2型糖尿病作用的GLP-1(7-37或7-36酰胺)具有4分钟或更短的生理活性半衰期(Kreymann等,1987)。因此,已经进行了各种关于具有抗DPP IV的GLP-1类似物的研究,并且已经进行了用Gly取代Ala(Deacon等,1998;Burcelin等,1999)或用Leu或D-Ala取代Ala(Xiao等,2001)的实验,从而保持它的活性的同时增加了对DPP IV的抗性。GLP-1的N末端氨基酸,His7对GLP-1的活性是重要的,并且作为DPP IV的目标。因此,美国专利第5545618号描述了用烷基或酰基修饰N末端,并且Gallwitz等描述了第7位His进行N甲基化或a甲基化,或者用整个His用咪唑取代来增加对DPP–IV的抗性并保持生理活性。
除了这些修饰,从希拉毒蜥蜴的唾液腺纯化的GLP-1类似物exendin-4(美国专利第5424686号)具有对DPP IV的抗性并比GLP-1具有更高的生理活性。因此,它具有比GLP-1的半衰期更长的2至4小时的体内半衰期。然而,仅适用增加DPP IV抗性的方法,生理活性不能被充分地保持,并且在使用商业可获得的exendin-4(exenatide)的情况下,它需要一天两次被注射给病人,这对病人仍然是很痛苦的。
这些促胰岛素肽具有一个问题,通常肽的大小很小,从而,它们不能在肾中被重新获得,并且它们随后被排出体外。因此,已经使用以化学方法在肽的表面添加例如聚乙二醇的具有高溶解度的聚合物来抑制在肾中的损失的方法。美国专利第692464号描述了PEG结合到exendin-4的赖氨酸残基来增加它的体内停留时间,然而,这种方法增加了PEG的分子量,从而增加了肽类药物的体内停留时间,同时随着分子量的增加,该肽类药物的浓度显著地减少,并且肽的反应性也降低了。因此,产量被不希望的降低了。
此外,一系列其它不同方法也已经用于修饰胰高血糖素样肽-1化合物的结构以提供体内更长的作用持续时间。
WO96/29342公开了其中亲本肽激素已经通过在C-端氨基酸残基或在N-端氨基酸残基引入亲脂性取代物而修饰肽激素衍生物。
WO98/08871公开了其中亲本肽的至少一个氨基酸残基连接有亲脂性取代物的GLP-1衍生物(liraglutide)。
WO99/43708公开了具有连接至C-端氨基酸残基的亲脂性取代物GLP-1(7-35)和GLP-1(7-36)衍生物。
WO00/34331公开了双酰化的GLP-1类似物。
WO 00/69911公开了用于注射进患者中的活化的促胰岛素肽,据认为在患者中它们与血液成分反应形成缀合物,从而据说提供体内更长的作用持续时间。
WO2012165915公开了一种胰岛素分泌肽衍生物,其中N末端残疾被选自脱氨基组胺酰基、4-咪唑并乙酰基、β-羧基咪唑并丙酰基取代,胰岛素分泌肽选自GLP-1、艾塞那肽-4、艾塞那肽-3等,但氨基酸被替换后活性不如Aib8-GLP-1(7-37)。
WO2006/097537公开了另一种酰化的GLP-1类似物(semaglutide),通过将第8位氨基酸突变为非天然氨基酸,如Aib,与WO98/08871的酰化的GLP-1(liraglutide)相比,具有更长的半衰期。
目前市场上获批的GLP-1药物主要有从蜥蜴唾液中分离出的Exenatide-4,以及采用脂肪酸,抗体Fc段或血清白蛋白修饰的人源GLP-1类似物。Exenatide-4半衰期太短,仅2-4小时,一天需要至少两次注射。诺和诺德公司的脂肪酸修饰的利拉鲁肽在降血红蛋白糖基化及降体重方面最有效且副作用较少,但其不足方面是体内半衰期只有13小时,需要每天给药。为了进一步延长体内半衰期,减少给药频率,近年来进一步采用氨基酸序列突变和FC、脂肪酸或白蛋白等修饰的长效GLP-1类似物已经被陆续开发。如礼来公司的杜拉鲁肽和诺和诺德公司即将上市的索玛鲁肽。这些长效化的GLP-1类似物在人体内的半衰期可被进一步延长,可实现每周给药一次的给药频率。由于GLP-1类似物需要长期注射给药,所以更长效期的药物的开发将具有更好的患者依从性及更大的市场竞争力。
现有技术中,通过Fc或脂肪酸的方式修饰而开发的长效GLP-1类似物,给药周期均被限定在1周或1周以内,本发明人独立地经过长期研究,令人意外地开发出了一种新的GLP肽类似物的缀合物,在相同实验条件下,与现有公认的最好的技术产品代表索玛鲁肽相比,在糖尿病老鼠模型上,其体内持续降糖活性时间可提高1倍左右,意味着在人体内可实现至少每周间隔给药、甚至每两周间隔或更长时间间隔的给药频率,并且能同时保证治疗特性,相当于、甚至优于进口昂贵的现有技术,具有良好的市场开发前景。
发明内容
本发明的目的在于提供一种新的GLP-1肽缀合物。另外,本发明还提供了该肽缀合物的制备方法、含该肽缀合物的药物以及在制备药物中的用途和中间体等。
具体而言,在第一方面,本发明提供了如下结构式所示的肽缀合物或其药学上可接受的盐,
其中,
B为
其中m是0、1、2或3;n是1、2或3;p是1-8的任意整数;
A是含HOOC(CH2)qCO-的酰基,其中q是4-38的整数。
优选在本发明第一方面的肽缀合物或其药学上可接受的盐中,
所述B的结构为
其中m是1,n是1;
A选自HOOC(CH2)14CO-、HOOC(CH2)15CO-、HOOC(CH2)16CO-、HOOC(CH2)17CO-、HOOC(CH2)18CO-、HOOC(CH2)19CO-、HOOC(CH2)20CO-、HOOC(CH2)21CO-和HOOC(CH2)22CO-,优选为HOOC(CH2)16CO-。
在本文中,如无矛盾或特别说明,(GLP-1或GLP-1(7-37)的)类似物可以与(GLP-1或GLP-1(7-37)的)衍生物互换使用,其与酰化的基团共同组合成肽缀合物。所述GLP-1(7-37)类似物可以与氨基酸序列如SEQ ID NO:1所示的GLP-1(7-37)相同,也可以具有一个氨基酸序列的不同(即一个氨基酸残基发生了取代、添加或缺失),或为具有两个氨基酸序列的不同,甚至为具有三个氨基酸序列的不同。具体地,所述GLP-1(7-37)类似物是将氨基酸序列如SEQ ID NO:1所示的GLP-1(7-37)中第7位His突变为非天然氨基酸4-咪唑并乙酰基(CA)、第8位氨基酸Ala突变为非天然氨基酸Aib,第34位氨基酸Lys突变为Arg。
本发明人惊奇地发现,通过这种突变方式获得的酰化的GLP-1类似物,与同样为酰化的GLP-1类产品,如索玛鲁肽(Semaglutide)相比,在糖尿病小鼠体内可以获得相对更长的活性持续时间,以及在相同时间点上更强的降糖活性。
在第二方面,本发明提供了制备本发明第一方面的肽缀合物或其药学上可接受的盐的方法,其包括:
(1)提供CA7-Aib8-Arg34-GLP-1类似物溶液,调整pH;
(2)向步骤(1)获得的溶液中加入三乙胺;
(3)将如下结构的脂肪酸溶于乙腈中;
其中m=1~3,n=1-3,优选为m=1,n=1;
(4)将步骤(2)获得的GLP-1类似物溶液与步骤(3)获得的脂肪酸溶液混合,静置;
(5)调节pH终止反应,酸沉,离心,得沉淀;
(6)向步骤(5)获得的沉淀中加水溶解,并加入氢氧化钠,震荡使沉淀溶解,脱保护,调节pH终止反应;
(7)分离纯化。
优选本发明第二方面的方法包括:
(1)提供浓度为4~6mg/ml的CA7-Aib8-Arg34-GLP-1类似物溶液,调整pH至9-12;
(2)向步骤(1)获得的溶液中加入0.1-0.5%(V/V)的三乙胺;
(3)称取不低于该GLP-1类似物2倍量(摩尔比)的如下结构的脂肪酸,优选为不低于3倍量的GLP-1类似物,溶于乙腈中;
其中m=1~3,n=1-3,优选为m=1,n=1;
(4)将步骤(2)获得的GLP-1类似物溶液与步骤(3)获得的脂肪酸溶液混合,于4℃静置一小时;
(5)加水稀释,调节pH至4.8终止反应,放于4℃静置酸沉,酸沉后4℃离心,得沉淀;
(6)向步骤(5)获得的沉淀中加水溶解,并加入1M氢氧化钠至终浓度100mM NaOH,震荡使沉淀溶解,置于室温静置脱保护,反应液调节pH至8.0-8.5终止反应;
(7)分离纯化。
在第三方面,本发明提供了一种药物组合物,其包括本发明第一方面的肽缀合物或其药学上可接受的盐,以及药学上可接受的辅料。
在本文中,如无矛盾或特别说明,药物、药物组合物和药物制剂(药剂)可以互换使用。在本文中,药学上可接受的辅料指无毒的填充剂、稳定剂、稀释剂、载体、溶剂或其他制剂辅料。例如,稀释剂、赋形剂,如微晶纤维素、甘露醇等;填充剂,如淀粉、蔗糖等;粘合剂,如淀粉、纤维素衍生物、藻酸盐、明胶和/或聚乙烯吡咯烷酮;崩解剂,如碳酸钙和/或碳酸氢钠;吸收促进剂,如季铵化合物;表面活性剂,如十六烷醇;载体、溶剂,如水、生理盐水、高岭土、皂粘土等;润滑剂,如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外,本发明的药物组合物优选为注射剂。
优选在本发明第三方面的药物组合物中,本发明第一方面的肽缀合物或其药学上可接受的盐以0.1mg/ml至25mg/ml的浓度存在,优选以0.1mg/ml至10.0mg/ml的浓度存在。
也优选本发明其中所述的本发明第三方面的药物组合物具有3.0至9.0的pH。其中,可进一步包含缓冲系统、防腐剂、表面张力剂、螯合剂、稳定剂和表面活性剂。在本发明的一个实施方案中,本发明第三方面的药物组合物是含水制剂。这种制剂通常是溶液或悬浮。本发明的具体实施方案中,该药物组合物是稳定的含水溶液。在本发明的另一个具体实施方案中中,该药物组合物是一种冻干制剂,在使用前医师或患者加入溶剂和/或稀释液至其中。
本发明第三方面的药物组合物也可以包括另一种或多种药理活性物质,与本发明第一方面的肽缀合物或其药学上可接受的盐组合使用。所述药理活性物质可以选自抗糖尿病药物、减肥药、食欲调节剂、抗高血压药、用于治疗和/或预防由糖尿病引发或与其相关的并发症的制剂以及用于治疗和/或预防由肥胖症引发或与其相关的并发症和障碍的药物化合物或组合物。这些药理活性物质的实例是:胰岛素、磺脲类、双胍、氯茴苯酸类、葡萄糖苷酶抑制剂、胰高血糖素拮抗剂、涉及刺激糖异生和/或糖原分解的肝脏酶的抑制剂、葡萄糖摄取调节剂、调节脂类代谢的化合物(如抗高血脂剂,如HGM、COA抑制剂)、胃抑制性多肽、降低食物摄取的化合物、RXR激动剂和作用于β细胞的ATP依耐性钾通道制剂、β阻滞剂如吲哚心安、萘心安和甲养乙心安、ACE抑制剂如贝那普利和卡托普利;CART激动剂、NPY拮抗剂、PYY激动剂、PYY2激动剂、PYY4激动剂、TNF激动剂、促皮质素释放因子激动剂、5HT、蛙皮素激动剂、神经节肽拮抗剂、生长激素、促甲状腺激素释放激素激动剂、瘦素激动剂、TRβ激动剂;组胺H3拮抗剂、脂肪酶/淀粉酶抑制剂、胃抑制性多肽激动剂或拮抗剂、胃泌素和胃泌素类似物等。
在第四方面,本发明提供了本发明第一方面的肽缀合物或其药学上可接受的盐在制备具有治疗或预防糖尿病、肥胖症、高血糖、血脂代谢障碍和/或非酒精性脂肪肝的药物中的应用。
优选在本发明第四方面的应用中,药物是本发明第三方面的药物组合物。
优选在本发明第四方面的应用中,糖尿病为2型糖尿病。
在第五方面,本发明提供了本发明第一方面的肽缀合物或其药学上可接受的盐在制备减少食物摄取、减少胰岛β-细胞凋亡、增加胰岛β-细胞功能和胰岛β-细胞数量和/或恢复胰岛β-细胞的葡萄糖敏感性的药物中的应用。
优选在本发明第五方面的应用中,药物是本发明第三方面的药物组合物。
另外,本发明还提供了本发明第一方面的肽缀合物的中间体及其应用等。
具体而言,在第六方面,本发明提供了如下结构式所示的化合物,
在第七方面,本发明提供了本发明第六方面的化合物在制备本发明第一方面的肽缀合物或其药学上可接受的盐中的应用。
在第八方面,本发明提供了GLP-1(7-37)类似物,其是CA7-Aib8-Arg34-GLP-1,即将氨基酸序列如SEQ ID NO:1所示的GLP-1(7-37)中第7位His突变为CA,第8位氨基酸Ala突变为Aib,第34位氨基酸Lys突变为Arg。
在第九方面,本发明提供了本发明第八方面的CA7-Aib8-Arg34-GLP-1在制备本发明第一方面的肽缀合物或其药学上可接受的盐中的应用。
本发明的有益效果在于:至少能每周间隔、甚至每两周间隔地给药,并且能同时保证临床治疗特性,相当于、甚至优于进口、昂贵的现有技术。
本发明通过下面实施例来进一步阐述,然而,所述的实施例不应理解为限制本专利的保护范围,在前面描述和下列实施例中公开的特征(个别地和它们的任何组合),可以是用于以基本不同形式实现本发明的材料。另外,本发明引用了公开文献,这些文献是为了更清楚地描述本发明,它们的全文内容均纳入本文进行参考,就好像它们的全文已经在本文中重复叙述过一样。
具体实施例
以下本文将通过具体的实施例来描述发明。如未特别指明之处,可根据本领域技术人员所熟悉的Fmoc固相合成方法以及CFDA的试验指引等所列方法来实施。其中,所用的试剂原料均为市售品,可以通过公开渠道购买获得。
实施例1CA7Aib8Arg34-GLP-1(7-37)的合成
CA7-GLP(7-37)的合成
Aib8Arg34-GLP-1(7-37)的合成
合成基本原理:在高分子树脂上,按多肽分子的氨基酸序列,从羧基端开始,依次将氨基酸连接成特定的多肽分子。
重复(缩合-洗涤-去保护-中和及洗涤-下一轮缩合)操作,达到所要合成的肽链长度,最后将肽链从树枝上裂解下来,经过纯化等处理,即得所要的多肽。
使用制造商提供的FastMoc UV方法,在Applied Biosystems 433肽合成仪上根据Fmoc策略合成0.25mmol或1.0mmol量级的经保护的肽酰树脂,所述的FastMoc UV方法采用在NMP(N-甲基吡咯烷酮)中的HBTU(2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸)或HATU(O-(7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸)介导的欧联,并且UV监控Fmoc保护基团的去保护。用于合成GLP-1肽酰胺的起始树脂是Rink-Amide树脂并且Wang或氯三苯甲基树脂用于具有羧基C端的GLP-1肽。除了非天然的氨基酸例如Fmoc-CA-OH(Fmoc-4-咪唑并乙酰基)、Fmoc-Aib-OH(Fmoc-氨基异丁酸)以外,使用的经保护的氨基酸衍生物是在适合用于ABI433A合成仪的预称量筒中提供的标准Fmoc-氨基酸,N端氨基酸在α-氨基处用Boc(叔丁氧羰基)保护。肽的合成在一些情况中可以通过利用在二肽酰胺键上用酸性条件下能够切割的基团保护的二肽来改善,所述的基团例如是但不限于2-Fmoc-氧-4甲氧苄基或2,4,6-三甲氧苄基。在肽中存在丝氨酸或苏氨酸的情况中,可以使用假脯氨酸(pseudoproline)二肽。
除去Fmoc-保护的方法:将树脂(0.25mmol)置于手动振荡器的滤瓶中并用N-甲基吡咯烷酮/二氯甲烷(1:1)(2x20ml)和N-甲基吡咯烷酮(1x20ml)、N-甲基吡咯烷酮中的20%哌啶溶液(3x20ml,每次10分钟)处理。用N-甲基吡咯烷酮(2x20ml)、N-甲基吡咯烷酮/二氯甲烷(1:1)(2x20ml)和二氯甲烷(2x20ml)洗涤树脂。
用于将肽从树脂裂解的方法:通过用三氟乙酸、水和三异丙基硅烷(95:2.5:2.5)的混合物在室温下搅拌180分钟将肽从树脂裂解。过滤裂解混合物并通过氮气流将滤出液浓缩为油状产物,用45ml乙醚从油状产物中沉淀出肽粗产物并用45ml乙醚洗涤3次。
纯化:将肽粗产物溶解于5ml 50%乙酸-水中并用水将其稀释成20ml并注入5μC-18硅石的20mm×250mm半制备柱上,随后在室温下将该柱用25-65%的梯度(在含有0.1%TFA的水中的CH3CN)以10ml/分钟洗脱50分钟,收集含有肽的级分,用水稀释洗脱无后冻干纯化的肽。
获得的终产物通过分析型RP-HPLC(保留时间)鉴定。
实施例2N-ε26-[2-(2-[2-(2-[4-(17-羧基十七烷酰氨基)-4(s)-羧基丁酰基氨基]乙氧基)乙氧基]乙酰氨基)乙氧基]乙氧基]乙酰基](CA7Aib8Arg34-GLP-1(7-37))肽的制备(CA7Aib8Arg34-GLP-1(7-37)-脂肪酸)
脂肪酸修饰:CA7Aib8Arg34-GLP-1(7-37)加水配为4~6mg/ml溶解液,加入1M氢氧化钠调整PH至11.0-11.5,摇匀使蛋白完全溶解,HPLC定量多肽浓度。按多肽与脂肪酸(结构如下)摩尔比1:3称取脂肪酸粉末溶于乙腈中。向多肽溶液中加入体积为千分之二的三乙胺,并与脂肪酸溶液混合,将混合液于4℃静置一小时。
样品加水稀释5倍,用1M柠檬酸(或10%乙酸)调PH至4.8终止反应,放于4度静置酸沉10min,酸沉后离心13000g,4℃离心30min,将沉淀放于-80℃保存
脂肪酸脱保护与纯化:向酸沉样品中加水溶解(终体积与修饰体积相同),加入1M氢氧化钠至终浓度100mM NaOH,震荡使沉淀溶解,置于室温静置脱保护30min,向反应液中滴入10%乙酸(或1M柠檬酸)调节PH至8.0-8.5终止反应。
用制备液相仪(岛津LC-8A)将终止后反应液按4ml/min流速,泵入事先用10mM乙酸铵,20%乙醇(平衡液3)平衡过的UniSil 10-120C18(购自纳微)进行浓缩。平衡液3淋洗后,再按0-100%洗脱液(10mM乙酸铵,80%乙醇)梯度洗脱,收集洗脱峰经RP-HPLC检测纯度约为90%。
洗脱峰用水稀释5倍,酸沉调整PH至4.80,4℃酸沉30min。离心后沉淀中加入DPBS缓冲液(PH7.0)复溶后-80℃冻存。
实施例3GLP-1多肽细胞活性筛选
GLP-1在体内首先刺激胰岛细胞产生cAMP之后cAMP进一步刺激产生胰岛素。为考察和比较不同设计的GLP-1序列的活性,cAMP刺激释放活性检测法(cAMP法)测定体外细胞活性,各不同样品取样浓度为10nM。结果如下。
表1不同肽的体外细胞活性
因为检测cAMP的酶联免疫采用的是竞争法,所以所得OD值与cAMP浓度成反比,OD值越小表明其活性越强,体外细胞活性最强的为CA7+Aib8-GLP-1类似物,为Aib8-GLP的1.7倍、Aib8-GLP的1.2倍,CA7-GLP活性最弱。
实施例4使用db/db小鼠的药效研究
糖尿病小鼠OGTT试验:选用15只周龄4~6周的db/db转基因糖尿病小鼠,分为三组,分别皮下注射溶酶(PBST溶液,10ml/kg)、CA+Aib肽-脂肪酸和索玛鲁肽剂量为0.3mg/kg体重。按照4h、1天、2天、3天、4天的时间间隔灌胃20%葡萄糖剂量为1g/kg体重,给糖前禁食过夜,并在给糖后0、0.5、1、2h分别尾尖取血并使用罗氏血糖试纸实时检测血糖值。测定结束后给食8h以上,尾尖取血并使用罗氏血糖试纸实时检测血糖值,并计算出0~120分钟内的血糖AUC(血糖~时间曲线下面积),算出血糖抑制率(表2)。
表2:不同GLP-1类似物肽对糖尿病小鼠体内降糖效果
P值:与阴性对照小鼠比较
从上表结果可以看出,对于糖尿病模型小鼠,非禁食血糖给药后的各个时间点上,AC+Aib肽-脂肪酸偶联物的降糖活性均要强于索玛鲁肽,对糖尿病小鼠的降糖活性明显更强;索玛鲁肽在第二天后,对糖尿病小鼠就活性明显下降,虽表现出一定降糖活性,但与正常组间差异已不显著,到第三天几乎没有降糖活性,而CA+Aib肽-脂肪酸给药后第二天活性依然很强,第三天也有一定的降糖活性,CA+Aib肽-脂肪酸在糖尿病小鼠体内维持持续降糖活性的时间更长。
序列表
<110> 杭州先为达生物科技有限公司
<120> 酰化的GLP-1衍生物
<130> 背景技术中
<140> 201810177659.2
<141> 2018-03-05
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 31
<212> PRT
<213> Homo sapiens
<400> 1
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
Claims (14)
1.如下结构式所示的肽缀合物或其药学上可接受的盐,
其中,
B为
其中m是0、1、2或3;n是1;A是HOOC(CH2)qCO-,其中q是16-38的整数。
2.权利要求1所述的肽缀合物或其药学上可接受的盐,其中,
所述B的结构为
其中m是1,n是1;
A选自HOOC(CH2)16CO-、HOOC(CH2)17CO-、HOOC(CH2)18CO-、HOOC(CH2)19CO-、HOOC(CH2)20CO-、HOOC(CH2)21CO-和HOOC(CH2)22CO-。
3.权利要求1所述的肽缀合物或其药学上可接受的盐,其中,A为HOOC(CH2)16CO-。
4.制备权利要求1至3任意一项所述的肽缀合物或其药学上可接受的盐的方法,其包括:
(1)提供CA7-Aib8-Arg34-GLP-1类似物溶液,调整pH;
(2)向步骤(1)获得的溶液中加入三乙胺;
(3)将如下结构的脂肪酸溶于乙腈中;
其中m=1~3,n=1;
(4)将步骤(2)获得的GLP-1类似物溶液与步骤(3)获得的脂肪酸溶液混合,静置;
(5)调节pH终止反应,酸沉,离心,得沉淀;
(6)向步骤(5)获得的沉淀中加水溶解,并加入氢氧化钠,震荡使沉淀溶解,脱保护,调节pH终止反应;
(7)分离纯化。
5.权利要求4所述的方法,其中,m=1,n=1。
6.权利要求4或5所述的方法,其包括:
(1)提供浓度为4~6mg/ml的CA7-Aib8-Arg34-GLP-1类似物溶液,调整pH至9-12;
(2)向步骤(1)获得的溶液中加入0.1-0.5%V/V的三乙胺;
(3)称取不低于该GLP-1类似物2倍量摩尔比的如下结构的脂肪酸,溶于乙腈中;
其中m=1~3,n=1;
(4)将步骤(2)获得的GLP-1类似物溶液与步骤(3)获得的脂肪酸溶液混合,于4℃静置一小时;
(5)加水稀释,调节pH至4.8终止反应,放于4℃静置酸沉,酸沉后4℃离心,得沉淀;
(6)向步骤(5)获得的沉淀中加水溶解,并加入1M氢氧化钠至终浓度100mM NaOH,震荡使沉淀溶解,置于室温静置脱保护,反应液调节pH至8.0-8.5终止反应;
(7)分离纯化。
7.权利要求6所述的方法,其中,m=1,n=1。
8.一种药物组合物,其包括权利要求1至3任意一项所述的肽缀合物或其药学上可接受的盐,以及药学上可接受的辅料。
9.权利要求1至3任意一项所述的肽缀合物或其药学上可接受的盐在制备具有治疗或预防糖尿病、肥胖症、高血糖、血脂代谢障碍和/或非酒精性脂肪肝的药物中的应用。
10.权利要求9所述的应用,其中,所述具有治疗或预防糖尿病、肥胖症、高血糖、血脂代谢障碍和/或非酒精性脂肪肝的药物是权利要求8所述的组合物。
11.权利要求9或10所述的应用,其中所述糖尿病为2型糖尿病。
12.权利要求1至3任意一项所述的肽缀合物或其药学上可接受的盐在制备减少胰岛β-细胞凋亡、增加胰岛β-细胞功能和胰岛β-细胞数量和/或恢复胰岛β-细胞的葡萄糖敏感性的药物中的应用。
13.权利要求12所述的应用,其中,所述减少胰岛β-细胞凋亡、增加胰岛β-细胞功能和胰岛β-细胞数量和/或恢复胰岛β-细胞的葡萄糖敏感性的药物是权利要求8所述的组合物。
14.如下结构式所示的化合物在制备权利要求1至3任意一项所述的肽缀合物或其药学上可接受的盐中的应用,
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