CN104672319A - N-末端氨基酸经修饰的促胰岛素释放肽衍生物 - Google Patents
N-末端氨基酸经修饰的促胰岛素释放肽衍生物 Download PDFInfo
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Abstract
本发明涉及具有高活性的N-末端氨基酸经修饰的促胰岛素释放肽以及包含其的药物组合物。本发明的促胰岛素释放肽衍生物显示出治疗作用，该活性并未在天然和其它促胰岛素释放肽类似物中发现。因此本发明的促胰岛素释放肽衍生物及含有其的药物组合物能有效用于治疗所述疾病。
Description
本申请是2008年7月16日提交的题为“N-末端氨基酸经修饰的促胰岛素释放肽衍生物”的中国专利申请200880024892.1的分案申请。
[技术领域]
本发明涉及一种具有改良的促胰岛素释放活性的促胰岛素释放肽衍生物。特别是，本发明涉及一种具有高稳定性和促胰岛素释放活性的N-末端氨基酸经修饰的促胰岛素释放肽。
[背景技术]
由于肽稳定性低，会被体内蛋白水解酶降解，所以其很容易变性，因而丧失活性，并且其具有相对小的大小，从而易于经过肾。因此，为了保持含有作为药物有效成分的肽的药物的血液水平和滴度，必须经常给病人施用肽药物以便维持所需要的血液水平和滴度。然而，肽药物通常是以可注射制剂的形式施用，而且为了保持生理活性肽的血液水平所采取的频繁施用会给病人带来严重的疼痛。为了解决这些问题，已经进行了许多研究。其中一项研究提出的方法是增加通过生物膜的肽药物的传输，于是肽药物通过口咽或鼻咽吸入转移进入机体。然而，这一方法与可注射制剂相比较，其体内转移效率非常低，所以仍难于保持肽药物的体内活性。
另一方面，许多研究针对改良肽药物的血液稳定性以及长时间保持药物在血液中的高浓度，从而最大化药物的药效。这种长效的肽药物制剂因此需要增加肽药物的稳定性并且要保持足够高水平的滴度而不会在病人中产生免疫反应。
作为稳定肽以及抑制蛋白水解酶降解的方法，已进行了一些实验来修饰对蛋白水解酶敏感的特异氨基酸序列。例如：GLP-1(7-37或7-36酰胺)，其功能是降低血液中葡萄糖浓度以治疗2型糖尿病，其生理活性半衰期短，大约有4分钟或更少(Kreymann等,1987)，这是由于二肽基肽酶IV(DPPIV)在第8位氨基酸(Ala)和第9位氨基酸(Asp)之间的裂解而使GLP-1滴度丧失。因此，许多研究在对DPP IV具有抗性的GLP-1类似物方面进行，有些实验用Gly取代Ala8(Deacon等,1998；Burcelin等,1999)，或用Leu或D-Ala取代Ala8(Xiao等，2001)，从而增加对DPP IV的抗性，同时保持其活性。GLP-1的N-末端氨基酸His7对于GLP-1的活性是关键的，而且还是DPP IV的靶。因此，美国专利No.5,545,618公开了用烷基或酰基修饰N-末端，Gallwitz等公开了将His7进行N-甲基化、或者α-甲基化、或用咪唑将整个His取代以增加对DPP IV的抗性并保持生理活性。尽管增加对二肽基肽酶的抗性从而改善了稳定性，但发现His7-修饰的衍生物在用相同浓度的较低的cAMP刺激时具有明显降低的受体亲合性(Gallwitz.等,Regulatory Peptide 79:93-102(1999),Regulatory Peptide 86:103-111(2000))。
除GLP-1之外，毒蜥外泌肽(exendin)是在Arizona和Northern Mexico常见的蜥蜴glia monster毒液中发现的肽。毒蜥外泌肽-3存在于珠毒蜥(Heloderma horridum)的毒液中，毒蜥外泌肽-4存在于毒蜥(Helodermasuspectum)的毒液中。毒蜥外泌肽与GLP-1有53％的高同源性(Goke等,J.Bio.Chem.,268:19650-55(1993))。据报道毒蜥外泌肽-4可以作用在特异性胰岛素分泌细胞上的GLP-1受体，以及作用在豚鼠胰腺的分散的腺泡细胞，胃的胃壁细胞，并且所述肽也可以在分离的胃中刺激促生长素抑制素的释放以及抑制促胃液素释放。此外，毒蜥外泌肽-3和毒蜥外泌肽-4被报道发现在胰腺腺泡细胞中刺激cAMP生成以及刺激胰腺腺泡细胞的淀粉酶释放。因为毒蜥外泌肽-4(美国专利No.5,424,686)具有His-Gly序列而不是作为GLP-1中二肽基肽酶底物的His-Ala，因此其对DPP IV具有抗性而且比GLP-1具有更高的生理活性。因此，它的体内半衰期比GLP-1长，有2到4个小时。虽然天然毒蜥外泌肽比GLP-1具有增加的体内半衰期，但是它的生理活性仍然不足以持久。例如：在商购可得毒蜥外泌肽-4(exenatide)的情况中，需要每天给病人注射两次，这对病人来说仍然是困难的。
为了改善天然毒蜥外泌肽的治疗效力，进行了制备其类似物、衍生物和变体方面的尝试。术语“类似物或变体”典型性地指通过在天然肽中或自天然肽中取代、缺失或插入一或多个氨基酸而制备的肽。术语“衍生物”指通过对天然肽的一或多个氨基酸进行烷基化、酰化、酯化或酰胺化制备的化学修饰的肽。
PCT申请PCT/US98/16387描述了新型毒蜥外泌肽激动剂化合物。通过要求其优先权，美国专利No.6956026公开了一种利用毒蜥外泌肽减少食物摄入的方法。此外，通过要求所述PCT申请的优先权，EP0996459公开了使用毒蜥外泌肽及其类似物以减少食物摄入，美国专利No.7157555公开了毒蜥外泌肽激动剂化合物。然而它们仅公开了毒蜥外泌肽类似物的一些序列。此外，也没有提到所述类似物的活性和性质，而且其也未得到详细说明书的支持。
[发明内容]
[技术问题]
因此，本发明发明人发现His1-修饰的毒蜥外泌肽衍生物比天然毒蜥外泌肽显示更高的血液稳定性以及促胰岛素释放活性，从而完成本发明。
[技术方案]
本发明的一个目的是提供具有改良的血液稳定性和促胰岛素释放活性的促胰岛素释放肽衍生物。
本发明另一个目的是提供用于治疗糖尿病的药物组合物，其包含具有改良的促胰岛素释放活性的促胰岛素释放肽衍生物。
[附图说明]
图1显示毒蜥外泌肽-4衍生物在血清中的稳定性。A:毒蜥外泌肽-4,D:DA-毒蜥外泌肽-4,H:HY-毒蜥外泌肽-4,C:CA-毒蜥外泌肽-4。
图2显示毒蜥外泌肽-4、毒蜥外泌肽-4衍生物和CA-毒蜥外泌肽-4的促胰岛素释放活性。
图3显示在糖尿病动物模型中毒蜥外泌肽-4和CA-毒蜥外泌肽-4的降血糖作用。
[最优方案]
一方面，本发明涉及具有改良的血液稳定性和促胰岛素释放活性的促胰岛素释放肽衍生物。
本发明的衍生物是具有化学修饰的N-末端组氨酸残基的衍生物或者N-末端组氨酸残基上具有化学修饰的氨基的衍生物。
优选地，本发明的促胰岛素释放肽是毒蜥外泌肽-4、毒蜥外泌肽-3或其衍生物。本文使用的术语“毒蜥外泌肽-4或毒蜥外泌肽-3衍生物”指的是对毒蜥外泌肽-4或毒蜥外泌肽-3取代、缺失和/或增加一或多个氨基酸所制备的肽，或具有一或多个化学修饰的氨基酸残基例如烷基化、酰化、酯化或酰胺化的肽，其活性与天然毒蜥外泌肽-4类似。
作为毒蜥外泌肽-3或毒蜥外泌肽-4衍生物的例子，可以通过缺失毒蜥外泌肽-4的C-末端或者用非天然氨基酸正亮氨酸取代毒蜥外泌肽-4的氨基酸所制备的毒蜥外泌肽-4衍生物在WO97/46584中公开。WO99/07404也公开了毒蜥外泌肽衍生物，其氨基酸用非天然氨基酸例如戊基甘氨酸、高脯氨酸或叔丁基甘氨酸取代，并且US2008/0119390公开了通过缺失毒蜥外泌肽-4的一些氨基酸制备的和通过用其它氨基酸残基取代毒蜥外泌肽-4的一些氨基酸残基制备的毒蜥外泌肽衍生物，其与天然毒蜥外泌肽-4相比由更短的氨基序列组成。这些出版物援引加入。
特别地，本发明也包括N-末端组氨酸的氨基脱去的衍生物(脱氨基-组氨酰衍生物)，其通过氨基被羟基取代制备的衍生物(β-羟基咪唑并丙酰衍生物)，其用二甲基残基修饰氨基制备的衍生物(二甲基-组氨酰衍生物)，其用羧基取代氨基制备的衍生物(β-羧基咪唑并丙酰衍生物)，或是其脱去带正电荷的氨基的衍生物，其中脱去其N-末端组氨酸残基的α碳以只保留咪唑并乙酰基(咪唑并乙酰衍生物)，以及其它N-末端氨基修饰的衍生物。
优选地，本发明提供了毒蜥外泌肽-4衍生物，其具有化学修饰的N-末端氨基或氨基酸残基，更优选地其中N-末端组氨酸残基的α氨基或α碳(毒蜥外泌肽-4的第一个氨基酸)被取代或去除的毒蜥外泌肽-4衍生物，更优选地除去N-末端氨基的脱氨基-组氨酰-毒蜥外泌肽-4(DA-毒蜥外泌肽-4)，用羟基取代氨基制备的β-羟基咪唑并丙酰-毒蜥外泌肽-4(HY-毒蜥外泌肽-4)，用羧基取代氨基制备的β-羧基咪唑并丙酰-毒蜥外泌肽-4(CX-毒蜥外泌肽-4)，用两个甲基残基修饰氨基制备的二甲基-组氨酰-毒蜥外泌肽-4(DM-毒蜥外泌肽-4)，以及脱去N-末端组氨酸残基的α碳的咪唑并乙酰-毒蜥外泌肽-4(CA-毒蜥外泌肽-4)。
本发明的一个特殊方面涉及含有下式1的氨基酸的促胰岛素释放肽衍生物。
R1-X-R2(式1)
其中R1选自由脱氨基-组氨酰、N-二甲基-组氨酰、β-羟基咪唑并丙酰、4-咪唑并乙酰和β-羧基咪唑并丙酰组成的组；
R2选自由-NH2、-OH或-Lys组成的组；
X选自由Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser、Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly和Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser组成的组；
Y选自由Lys、Ser和Arg组成的组；
Z选自由Lys、Ser和Arg组成的组。
优选促胰岛素释放肽衍生物具有式1，其中R1选自由脱氨基-组氨酰、N-二甲基组氨酰、β-羟基咪唑并丙酰、4-咪唑并乙酰和β-羧基咪唑并丙酰组成的组，Y为Lys或Ser，Z为Lys，R2为-NH2。
本发明的另一个特殊方面涉及含有下式2的氨基酸的促胰岛素释放肽衍生物。
R3-X'-R4(式2)
其中R3是4-咪唑并乙酰基，
X'为Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser或Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly；
R4为-NH2；
Y选自由Lys、Ser和Arg组成的组；
Z选自由Lys、Ser和Arg组成的组。
就活性而言，毒蜥外泌肽-4的N-末端组氨酸残基中的化学修饰与在其它促胰岛素释放肽GLP-1中具有不同的作用。GLP-1的N-末端组氨酸残基中的化学修饰例如α-甲基-GLP-1、N-甲基-GLP-1或者imi-GLP-1预期抑制二肽基肽酶的降解，从而增加稳定性，并且报道了降解速率的实际降低。然而，与天然的GLP-1相比，也报道了用较低cAMP刺激时它们具有相对降低的受体亲和性。
相反，由于毒蜥外泌肽-4不被二肽基肽酶裂解，因此难以预测在N-末端组氨酸残基上的化学修饰对活性的作用，尤其是其对受体亲合性和血糖浓度的作用。
因此，本发明提供了具有化学修饰的N-末端组氨酸残基或具有化学修饰的N-末端组氨酸残基的氨基的毒蜥外泌肽-4衍生物，与天然毒蜥外泌肽-4相比其展现出出乎预料之外的极好的促胰岛素释放活性。与毒蜥外泌肽-4，这些衍生物展现出极好的体外血液稳定性和促胰岛素释放活性(图2)。实际上，糖尿病db/db小鼠中发现其与天然毒蜥外泌肽-4相比表现出极好的降血糖浓度的作用(图3)。人们认为由于N-末端组氨酸残基的氨基的修饰导致的净电荷的改变或者组氨酸残基大小的改变导致了对血液中蛋白水解攻击的敏感性的差异并影响了受体亲合性。然而，仍需要对此进行更广泛的分子水平的研究。这种性质预期可以最大化毒蜥外泌肽-4固有的促胰岛素释放活性，即对2型糖尿病的治疗作用，并预期诱导降低食物摄入，延迟胃排空等等。
毒蜥外泌肽-4衍生物包括本发明的脱氨基-组氨酰-毒蜥外泌肽-4(DA-毒蜥外泌肽-4)、β-羟基咪唑并丙酰-毒蜥外泌肽-4(HY-毒蜥外泌肽-4)、β-羧基咪唑并丙酰-毒蜥外泌肽-4(CX-毒蜥外泌肽-4)、二甲基-组氨酰-毒蜥外泌肽-4(DM-毒蜥外泌肽-4)以及咪唑并乙酰-毒蜥外泌肽-4(CA-毒蜥外泌肽-4)通过脱去或取代N-末端组氨酸残基的α氨基或者通过脱去N-末端组氨酸残基的α碳制备。所以，只要它们的活性能够保持，其它的氨基酸顺序并没有限定。而且，对于本领域技术人员显而易见的是可以通过典型方法修饰毒蜥外泌肽-4衍生物，以增强其治疗作用，以优于天然毒蜥外泌肽-4，所述方法包括多聚物例如PEG和糖链的修饰和与白蛋白或运铁蛋白融合。
本发明另一个方面提供了用于治疗糖尿病的药物组合物，其包含促胰岛素释放肽衍生物。
本发明使用的术语“施用”表示通过合适的方法将预定量的物质导入病人。本发明的缀合物可以通过任何通常途径施用，只要它能到达所希望的组织。可以考虑多种施用方式，包括腹膜内、静脉内、肌内、皮下、透皮、口服、局部、鼻内、肺内和直肠内，但是本发明不限于这些举例说明的施用方式。然而，因为肽在口服施用时会被消化，为了保护不在胃里被降解，用于口服施用的组合物的活性成分应被包衣或者配制。优选所述组合物以可注射形式施用。此外，本发明的药物组合物可以利用某些能够将活性成分运输至靶细胞的装置施用。
包含本发明的缀合物的药物组合物还包含药学上可接受的载体。对于口服施用，药学上可接受的载体可包括粘合剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、着色剂以及芳香剂。对于注射制剂，药学上可接受的载体可包括缓冲剂、防腐剂、止痛剂、增溶剂、等渗剂和稳定剂。对于局部施用制剂，药学上可接受的载体可包括基质、赋形剂、润滑剂和防腐剂。本发明的药物组合物可以与上述药学上可接受的载体配制成多种剂型。例如，对于口服施用，药物组合物可以配制成片剂、锭剂、包囊、酏剂、悬浮剂、糖浆或圆片。对于注射制剂，药物组合物可以配制成单位剂量形式，如多剂量容器或以安瓿作为单一剂量剂型。药物组合物也可以配制成溶液、悬浮液、片剂、丸剂、包囊和长效制剂。
另一方面，用于药物制剂的载体、赋形剂以及稀释剂的例子包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、刺槐橡胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟苯丙酯、滑石、硬脂酸镁和矿物油。此外，药物制剂可进一步包括填充剂、抗凝剂、润滑剂、湿润剂、芳香剂和杀菌剂。
本发明的药物组合物的施用频率和剂量通过几个有关因素决定，包括治疗疾病的类型，施用途径，患者年龄、性别、体重以及患病严重程度，以及作为活性组分的药物类型。因为本发明的药物组合物具有良好的体内效力和滴度持续时间，其可以显著地减少本发明药物的施用频率和剂量。
本发明的促胰岛素释放衍生物并没有被前人所公开，或者仅是泛泛公开而没有揭示特异的氨基酸序列，并且它们的活性从来没有与天然毒蜥外泌肽-4、其它的衍生物和变体相比较。所以，不能预料到N-末端的α氨基或α碳被取代或缺失的毒蜥外泌肽-4衍生物具有异常极好的活性。因此，本发明的促胰岛素释放肽衍生物的极好的血清稳定性以及促胰岛素释放活性最大化了对2型糖尿病的治疗作用。
[发明方式]
通过以下实施例更透彻地阐明本发明，但实施例仅是说明目的，不能解释为对于本发明的限制。
实施例1.毒蜥外泌肽-4衍生物的血浆稳定性
为了测定毒蜥外泌肽-4衍生物的血浆稳定性，将天然毒蜥外泌肽-4和毒蜥外泌肽-4衍生物的每一个暴露于血浆，利用反相HPLC测定未变性的剩余蛋白质的量以进行依赖于暴露时间的变性测试。
在本实验中，为分析暴露于血浆的样品，将血浆混合样品去蛋白，然后再分析。
将天然毒蜥外泌肽-4、脱氨基-组氨酰-毒蜥外泌肽-4(DA-毒蜥外泌肽-4)、β-羟基咪唑并丙酰-毒蜥外泌肽-4(HY-毒蜥外泌肽-4)、β-羧基咪唑并丙酰-毒蜥外泌肽-4(CX-毒蜥外泌肽-4)、二甲基-组氨酰-毒蜥外泌肽-4(DM-毒蜥外泌肽-4)和咪唑并乙酰-毒蜥外泌肽-4(CA-毒蜥外泌肽-4)分别制备成浓度为1mg/ml。每种毒蜥外泌肽-4衍生物样品取200μl与200μl大鼠血清混合，37℃下进行反应，在每个取样时间，每个样品0小时、1小时、2小时、4小时、6小时、8小时、18小时和24小时的每个时间点取出100μl。将冰浴冷却的400μl甲醇加入至100μl的样品中以终止反应，然后涡旋20秒。每种混合物在15,000rpm下离心30分钟，取上清液进行分析。
反相HPLC用C18柱用于ACN中的TFA梯度作为流动相进行。
结果由毒蜥外泌肽-4的主峰面积与总峰面积的比率(％)计算得出，以时间点0小时的每个衍生物的结果作为100％，得出根据随着暴露时间增加主峰面积比率减小的模式做出的图。
直至时间点24小时时，天然毒蜥外泌肽-4的纯度降低大约70％，三种衍生物(D、H、C形式)的纯度分别降低大约77％、78％、77％(图1)。
实施例2.测量毒蜥外泌肽-4衍生物的体外活性
为了测定包括脱氨基-组氨酰-毒蜥外泌肽-4的毒蜥外泌肽-4衍生物的效力，检测它们的体外细胞活性。天然毒蜥外泌肽-4和毒蜥外泌肽-4衍生物由American Peptide Corporation合成。分离通常用来测量GLP-1体外活性的胰岛瘤细胞或胰岛，在经GLP-1处理后分析cAMP产生的变化。
在本实验中，利用已知是大鼠胰岛瘤细胞且具有GLP-1受体(因此通常被用来测量GLP-1的体外活性)的RIN-m5F(ATCC CRL-11605)测量体外活性。用不同浓度的GLP-1、天然毒蜥外泌肽-4以及包括N-末端-α-脱氨基-组氨酰-毒蜥外泌肽-4的毒蜥外泌肽-4衍生物处理RIN-m5F细胞，测定由于测试材料导致的cAMP生成以确定EC50值。
表1
实施例3.测量毒蜥外泌肽-4衍生物的促胰岛素释放活性
毒蜥外泌肽-4衍生物的促胰岛素释放活性在RINm5F细胞中进行比较。解冻RINm5F细胞，亚培养至少一次，然后以1x105细胞/孔的密度接种至具有含FBS(Gibco,#11082)的培养基的96-孔板中。然后在5％CO2保温箱中37℃下培养细胞48小时。用含0.5％FBS的新配培养基替换培养基，然后保温1小时。用含0.5％FBS和葡萄糖的培养基稀释每个CA-毒蜥外泌肽-4以及毒蜥外泌肽-4(byetta，Amylin)以得到度为10nM到0.001nM。除了毒蜥外泌肽样品，制备稀释的溶液并用作对照组。去除RINm5F细胞的培养基，添加准备好的样品，然后在5％CO2保温箱中37℃下培养1小时。然后，回收各个孔中的培养基。用大鼠胰岛素ELISA试剂盒(Mercodia)测定所回收培养基中的胰岛素浓度，结果示于图2和表2。
表2
| 样品 | 最大胰岛素分泌与对照组的比率 |
| CA毒蜥外泌肽-4 | 83.6％ |
| 毒蜥外泌肽-4 | 43.3％ |
如图2和表2所示，毒蜥外泌肽-4衍生物之一CA毒蜥外泌肽-4在相同浓度下展现出比天然毒蜥外泌肽-4高大约2倍的促胰岛素释放活性。
实施例3.毒蜥外泌肽-4衍生物的体内效力的比较
为了测定毒蜥外泌肽-4衍生物的体内效力，与天然毒蜥外泌肽-4相比较，在糖尿病动物模型中测量了它们的降血糖作用。db/db小鼠(Jackson Lab,10-12周龄)被禁食2小时，然后分别以0.01-1000mcg.kg的量施用毒蜥外泌肽-4和CA毒蜥外泌肽-4。1小时后，从尾血管收集血样以用血度仪测定血糖水平。毒蜥外泌肽-4、CA毒蜥外泌肽-4以及载体通过皮下途径施用，在每个浓度计算与载体相比的血糖变化％。在各浓度下，用Prism程序计算降血糖作用的ED5O(图3，表3)。
表3
| 样品 | ED50(mcg/kg) | R2 |
| CA毒蜥外泌肽-4 | 2.30 | 0.99 |
| 毒蜥外泌肽-4 | 9.92 | 0.98 |
如图3和表3所示，在糖尿病动物模型中CA毒蜥外泌肽-4显示出比天然毒蜥外泌肽-4高大约5倍的降血糖作用。
[工业实用性]
本发明的促胰岛素释放肽衍生物最大化了毒蜥外泌肽的固有的促胰岛素释放活性，即对于2型糖尿病的治疗作用，并且诱导食物摄入的降低，延迟胃排空等等，优于天然及其它促胰岛素释放肽类似物。所以，本发明的促胰岛素释放肽衍生物及包含其的药物组合物可有效地治疗上述疾病。
Claims (6)
1.毒蜥外泌肽-4衍生物，其中天然毒蜥外泌肽-4的N-末端组氨酸残基被选自N-二甲基-组氨酰基、β-羟基咪唑并丙酰基和4-咪唑并乙酰基的材料取代。
2.权利要求1所述的毒蜥外泌肽-4衍生物，其中所述毒蜥外泌肽-4衍生物由下式1所示的氨基酸组成：
R1-X-R2 (式1)
其中R1选自N-二甲基-组氨酰基、β-羟基咪唑并丙酰基和4-咪唑并乙酰基；
R2选自-NH2或-OH；
X为Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser或Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Y-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z-Asn-Gly-Gly；
Y选自Lys、Ser和Arg；以及
Z选自Lys、Ser和Arg。
3.权利要求2所述的毒蜥外泌肽-4衍生物，其中R1为N-二甲基-组氨酰基，Y为Lys或Ser，Z为Lys，及R2为-NH2。
4.权利要求2所述的毒蜥外泌肽-4衍生物，其中R1为4-咪唑并乙酰基，Y为Lys或Ser，Z为Lys，及R2为-NH2。
5.权利要求2所述的毒蜥外泌肽-4衍生物，其中R1为β-羟基咪唑并丙酰基，Y为Lys或Ser，Z为Lys，及R2为-NH2。
6.一种用于治疗糖尿病的药物组合物，其包含权利要求1所述的毒蜥外泌肽-4衍生物。
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| US99115507P | 2007-11-29 | 2007-11-29 | |
| US60/991,155 | 2007-11-29 | ||
| CN200880024892A CN101778863A (zh) | 2007-07-16 | 2008-07-16 | N-末端氨基酸经修饰的促胰岛素释放肽衍生物 |
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Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009019027A (ja) * | 2007-07-16 | 2009-01-29 | Hanmi Pharmaceutical Co Ltd | アミノ末端のアミノ酸が変異したインスリン分泌ペプチド誘導体 |
| PL2408800T3 (pl) | 2009-03-20 | 2016-11-30 | Sposób wytwarzania koniugatu miejscowo-specyficznego, fizjologicznie aktywnego polipeptydu | |
| KR20120116942A (ko) | 2009-11-23 | 2012-10-23 | 아밀린 파마슈티칼스, 인크. | 폴리펩티드 접합체 |
| KR101382593B1 (ko) * | 2010-07-21 | 2014-04-10 | 한미사이언스 주식회사 | 신규한 지속형 글루카곤 결합체 및 이를 포함하는 비만 예방 및 치료용 약학적 조성물 |
| CN103370083B (zh) | 2010-09-28 | 2016-11-16 | 艾米琳制药有限责任公司 | 具有增强的作用持续时间的工程化多肽 |
| EA032917B1 (ru) | 2010-09-28 | 2019-08-30 | Амилин Фармасьютикалс, Ллк | Сконструированные полипептиды, характеризующиеся увеличенной продолжительностью действия |
| WO2012162547A2 (en) | 2011-05-25 | 2012-11-29 | Amylin Pharmaceuticals, Inc. | Long duration dual hormone conjugates |
| UA113626C2 (xx) | 2011-06-02 | 2017-02-27 | Композиція для лікування діабету, що містить кон'югат інсуліну тривалої дії та кон'югат інсулінотропного пептиду тривалої дії | |
| JP6006309B2 (ja) | 2011-07-08 | 2016-10-12 | アミリン・ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニーＡｍｙｌｉｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｌｌｃ | 作用持続期間が増大し、免疫原性が減少した操作されたポリペプチド |
| CN103957926B (zh) | 2011-07-08 | 2018-07-03 | 安米林药品有限责任公司 | 具有增强的作用持续时间和降低的免疫原性的工程改造的多肽 |
| KR20130049671A (ko) | 2011-11-04 | 2013-05-14 | 한미사이언스 주식회사 | 생리활성 폴리펩타이드 결합체 제조 방법 |
| AR090281A1 (es) | 2012-03-08 | 2014-10-29 | Hanmi Science Co Ltd | Proceso mejorado para la preparacion de un complejo polipeptidico fisiologicamente activo |
| CN103130889A (zh) * | 2012-06-15 | 2013-06-05 | 中国药科大学 | 一种Exendin-4类似物及其制备方法和应用 |
| US10441665B2 (en) | 2012-07-25 | 2019-10-15 | Hanmi Pharm. Co., Ltd. | Liquid formulation of long acting insulinotropic peptide conjugate |
| AR094821A1 (es) | 2012-07-25 | 2015-09-02 | Hanmi Pharm Ind Co Ltd | Formulación líquida de un conjugado de péptido insulinotrópico de acción prolongada |
| AR092862A1 (es) | 2012-07-25 | 2015-05-06 | Hanmi Pharm Ind Co Ltd | Formulacion liquida de insulina de accion prolongada y un peptido insulinotropico y metodo de preparacion |
| KR20140088837A (ko) * | 2013-01-03 | 2014-07-11 | 한미약품 주식회사 | Ｎ-말단 전하가 변형된 인슐린 분비 펩티드 유도체 |
| AR096890A1 (es) | 2013-07-12 | 2016-02-03 | Hanmi Pharm Ind Co Ltd | Conjugando fc de inmunoglobulina, que mantiene la afinidad de unión del fragmento fc de la inmunoglobulina a fcrn |
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| JP6987741B2 (ja) | 2015-07-24 | 2022-01-05 | ハンミ ファーマシューティカル カンパニー リミテッド | 生理活性ポリペプチド結合体の製造方法 |
| UY36870A (es) | 2015-08-28 | 2017-03-31 | Hanmi Pharm Ind Co Ltd | Análogos de insulina novedosos |
| US20190055279A1 (en) * | 2015-10-28 | 2019-02-21 | Tufts University | Novel polypeptides with improved proteolytic stability, and methods of preparing and using same |
| CN110546161B (zh) | 2016-09-23 | 2024-01-26 | 韩美药品股份有限公司 | 对胰岛素受体具有降低的结合力的胰岛素类似物及其用途 |
| JP2019536823A (ja) | 2016-12-05 | 2019-12-19 | ハンミ ファーマシューティカル カンパニー リミテッド | 免疫反応が弱化された結合体 |
| CN110545849A (zh) | 2017-02-03 | 2019-12-06 | 韩美药品株式会社 | 具有增加的持续性的生理活性物质的缀合物及其应用 |
| CN110536899B (zh) | 2017-03-23 | 2023-12-12 | 韩美药品株式会社 | 对胰岛素受体具有降低的亲和力的胰岛素类似物复合物及其用途 |
| WO2022266467A2 (en) | 2021-06-17 | 2022-12-22 | Dana-Farber Cancer Institute, Inc. | Recombinant histone polypeptide and uses thereof |
| KR20230000682A (ko) | 2021-06-25 | 2023-01-03 | 한미약품 주식회사 | 심혈관 질환 또는 신장 기능장애 발생의 위험을 감소시키기 위한 에페글레나타이드 |
| KR20230010571A (ko) | 2021-07-12 | 2023-01-19 | 한미약품 주식회사 | Glp-1 유사체를 함유하는 경구 투여 제형 조성물 |
| WO2023194390A1 (en) * | 2022-04-08 | 2023-10-12 | Danmarks Tekniske Universitet | Histidine methyltransferase for increased peptide and protein stability |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157555B1 (en) * | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
Family Cites Families (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7A (en) * | 1836-08-10 | Thomas blanchard | ||
| US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
| US5424286A (en) * | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
| US5424686A (en) | 1994-04-20 | 1995-06-13 | Philips Electronics North America Corporation | Negative-resistance-compensated microwave buffer |
| US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
| AU723694B2 (en) | 1996-06-05 | 2000-08-31 | Roche Diagnostics Gmbh | Exendin analogues, processes for their preparation and medicaments containing them |
| JP2002507188A (ja) | 1996-08-30 | 2002-03-05 | イーライ・リリー・アンド・カンパニー | グルカゴン様ペプチド―１（ｇｌｐ―１）またはその同族体における外科処置後の異化変調を防止するための使用 |
| US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
| RU2214419C2 (ru) * | 1996-08-30 | 2003-10-20 | Ново Нордиск А/С | Glp-1 производные |
| US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
| WO1998030231A1 (en) | 1997-01-07 | 1998-07-16 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the reduction of food intake |
| EP1019077B2 (en) | 1997-08-08 | 2010-12-22 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
| EP1938831A1 (en) | 1997-08-08 | 2008-07-02 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
| US7220721B1 (en) * | 1997-11-14 | 2007-05-22 | Amylin Pharmaceuticals, Inc. | Exendin agonist peptides |
| US6703359B1 (en) * | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
| EP1056775B1 (en) * | 1998-02-27 | 2010-04-28 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
| EA200100289A1 (ru) | 1998-08-28 | 2001-10-22 | Эли Лилли Энд Компани | Способ введения инсулинотропных пептидов |
| KR20080085082A (ko) * | 2000-12-07 | 2008-09-22 | 일라이 릴리 앤드 캄파니 | Ｇｌｐ-1 융합 단백질 |
| IL141647A0 (en) * | 2001-02-26 | 2002-03-10 | Yeda Res & Dev | Synthetic human peptides and pharmaceutical compositions comprising them for the treatment of systemic lupus erythematosus |
| US6573237B2 (en) * | 2001-03-16 | 2003-06-03 | Eli Lilly And Company | Protein formulations |
| JP4417113B2 (ja) | 2002-02-20 | 2010-02-17 | エミスフェアー・テクノロジーズ・インク | Ｇｌｐ−１分子の投与方法 |
| BR0314996A (pt) * | 2002-10-02 | 2005-08-09 | Zealand Pharma As | Composição, composição farmaceuticamente aceitável, método para produzir a composição, métodos para estabilizar a exendina-4 (1-39) ou uma sua variante, derivado ou análogo contra a degradação, antes, durante ou após o uso pretendido, para tratar doenças, para tratar de estados de doenças associados com nìveis elevados de glicose do sangue, para a regulação dos nìveis de glicose do sangue, para a regulação do esvaziamento gástrico, para estimular a liberação de insulina em um mamìfero para reduzir o nìvel de glicose do sangue em um mamìfero, para reduzir o nìvel de lipìdeos plasmáticos em um mamìfero, para reduzir a mortalidade e a morbidez após o infarto miocárdico em um mamìfero, para estimular a liberação de insulina em um mamìfero, e para produzir uma exendina (1-39) estabilizada, e, exendina (1-39) estabilizada |
| US7790681B2 (en) * | 2002-12-17 | 2010-09-07 | Amylin Pharmaceuticals, Inc. | Treatment of cardiac arrhythmias with GLP-1 receptor ligands |
| EP1610811A4 (en) * | 2002-12-17 | 2008-03-26 | Amylin Pharmaceuticals Inc | PREVENTING AND TREATING CARDIAC ERRORS |
| JP2006514649A (ja) * | 2003-12-17 | 2006-05-11 | アミリン・ファーマシューティカルズ，インコーポレイテッド | 腎症の治療および予防のための組成物 |
| TW200611704A (en) * | 2004-07-02 | 2006-04-16 | Bristol Myers Squibb Co | Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions |
| AU2006224537A1 (en) * | 2005-03-18 | 2006-09-21 | Novo Nordisk A/S | Extended GLP-1 compounds |
| CA2619426C (en) * | 2005-08-19 | 2016-06-21 | Amylin Pharmaceuticals, Inc. | Exendin for treating diabetes and reducing body weight |
| US20100016547A1 (en) | 2005-11-30 | 2010-01-21 | Takaomi Ito | Glycosilated Peptide and Medicine Comprising It as an Effective Ingredient |
| EP2066337A2 (en) | 2006-08-04 | 2009-06-10 | Amylin Pharmaceuticals, Inc. | Use of exendins, exendin agonists and glp-1 receptor agonists for altering the concentration of fibrinogen |
| JP2008169195A (ja) * | 2007-01-05 | 2008-07-24 | Hanmi Pharmaceutical Co Ltd | キャリア物質を用いたインスリン分泌ペプチド薬物結合体 |
| WO2008145721A2 (en) * | 2007-06-01 | 2008-12-04 | Novo Nordisk A/S | N-terminal modification of polypeptides for protection against degradation by aminopeptidases |
| JP2009019027A (ja) * | 2007-07-16 | 2009-01-29 | Hanmi Pharmaceutical Co Ltd | アミノ末端のアミノ酸が変異したインスリン分泌ペプチド誘導体 |
| US9816387B2 (en) | 2014-09-09 | 2017-11-14 | United Technologies Corporation | Attachment faces for clamped turbine stator of a gas turbine engine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157555B1 (en) * | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
Non-Patent Citations (2)
| Title |
|---|
| 朱敏等: "重组exendin-4对遗传性胰岛素抵抗糖尿病大鼠糖耐量的影响", 《中华老年医学杂志》 * |
| 谭兴容等: "Exendin-4与糖尿病治疗", 《重庆医学》 * |
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