CN116970062B - 一种超长效glp-1多肽衍生物及其制备方法和用途 - Google Patents
一种超长效glp-1多肽衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种超长效GLP‑1多肽衍生物或其盐,所述超长效GLP‑1多肽衍生物为式(I)所示,主链中有且仅有一个X2,其侧链的氨基连接式(II)所示支链的酰基并形成酰胺,所述超长效GLP‑1多肽衍生物或其盐及其药物制剂在治疗和/或预防II型糖尿病、糖耐量受损、I型糖尿病、肥胖相关疾病、代谢综合征、非酒精性脂肪肝炎、非酒精性脂肪肝病、神经退行性疾病等的应用。7H‑Aib‑X1‑10G‑T‑F‑T‑S‑D‑V‑S‑S‑Y‑20L‑E‑G‑Q‑A‑25A‑X2‑E‑F‑I‑30A‑W‑L‑V‑X3‑35G‑R‑Z(I)
Description
技术领域
本发明属于医药技术领域,尤其涉及一种超长效GLP-1多肽衍生物及其制备方法和用途。
背景技术
胰高血糖素样肽-1(GLP-1)是由人肠道L细胞分泌的一种肽类激素,能够促进胰岛素的分泌、抑制胰高血糖素的分泌,具有降低血糖浓度的功效,被用于II型糖尿病和肥胖的治疗。然而天然GLP-1在体内不稳定,易被二肽基肽酶-IV(DPP-IV)快速降解,半衰期不到2分钟。GLP-1的功能是由GLP-1受体(GLP-1R)介导的。GLP-1R广泛分布于胰腺、肝脏、肾脏、大脑等全身多个组织和器官。GLP-1受体激动剂或药物降糖的生理作用及其机制为可双向调节胰岛α细胞和β细胞的分泌功能,促进胰岛β细胞的分化增殖和抑制其凋亡、减轻炎症细胞浸润等方式来改善胰岛β细胞的功能从而使β细胞数增多,增加胰岛β细胞对葡萄糖的敏感性,促进葡萄糖依赖性的胰岛素的分泌,抑制胰高血糖素的释放。GLP-1受体激动剂或药物对心血管***有益的生理作用及其机制为减少氧化应激,促进NO释放,改善内皮功能,抑制炎症反应,减少左室重构,延缓AS进展,降低收缩压、肺毛细血管楔压,增加心肌梗死后的心肌挽救率,增加自噬,减少心肌损伤,调节心肌细胞内钙离子浓度,避免心肌细胞凋亡,改善代谢因素及年龄诱导的心肌纤维化,从而改善心血管***功能并降低心血管死亡、非致死性心肌梗死或非致死性卒中发生率。GLP-1受体激动剂或药物减肥的生理作用及其机制为:中枢神经***可以合成GLP-1,且GLP-1受体在脑内广泛分布,意即GLP-1既是一种胃肠道激素,也是一种脑神经肽,其通过中枢神经***介导抑制胃肠道的分泌和运动(尤其是延缓胃排空)、增加饱腹感、影响食物摄取等作用,从而达到降糖减重的双重目的。GLP-1受体激动剂或药物护肝的生理作用及其机制为肝细胞中存在GLP-1受体,GLP-1受体激动剂或药物可激活肝脏的GLP-1R,直接调节肝脏脂质的代谢、氧化应激及内质网应激引起的炎症反应,降低肝脏的内脏脂肪含量,从而保护肝细胞,进一步预防和延缓非酒精性脂肪肝的发生与发展。GLP-1受体激动剂或药物强脑的生理作用及其机制为可激活脑部的GLP-1R,增强神经生长因子介导神经细胞分化,刺激神经触突生长,减少血脑屏障对葡萄糖的转运,促进脑内多巴胺代谢正常化并使多巴胺神经元增加。
索玛鲁肽,中文名又作司美格鲁肽,英文名称为Semaglutide,是由丹麦诺和诺德公司开发生产的一种新型长效胰高血糖素样肽-1(GLP-1)类似物,具有降血糖、减肥和保护心血管等临床功效,可能还对NASH(非酒精性脂肪肝)、AD(阿尔茨海默症)有治疗意义。降糖和减少心血管风险的注射用索马鲁肽Ozempic、降糖的口服药索马鲁肽Rybelsus、减肥的注射用索马鲁肽Wegovy在全球不同国家陆续获批上市。索玛鲁肽的Lys侧链经AEEA(中文名2-(2-(2-氨基乙氧基)乙氧基)乙酸)、Glu和十八碳二羧酸修饰后,亲水性大大提高、与白蛋白的结合力增强;同时N端第2位的Ala突变为Aib后,有效的避免了被DPP-IV酶解而失活,注射用索马鲁肽Ozempic人均半衰期达到6.3天,患者每周只需注射一次。
Jesper Lau等(Discovery of the Once-Weekly Glucagon-Like Peptide-1(GLP-1)Analogue Semaglutide,J.Med.Chem,2015,58:7370-7380)和Lotte Bj erreKnudsen与Jesper Lau等(The Discovery and Development of Liraglutide andSemaglutide,Front Endocrinol.,2019,10:155)详细阐述了对多肽的支链修饰进行不同地改造达到了半衰期延长同时保持多肽亲和力的研究过程,其中索马鲁肽及其他GLP-1衍生物内容分别在中国专利CN101133082B和世界专利WO2006/097537 A2中体现。JinhuaZhang等(Design,synthesis and biological evaluation of double fatty chain-modified glucagon-like peptide-1conjugates,Bioorg.Med.Chem.,2021,44:116291)和Jing Ha等(Novel fatty chain-modified glucagon-like peptide-1conjugates withenhanced stability and prolonged in vivo activity,Biochem.Pharmacol.,2013,86:297-308)等均尝试了新的支链修饰方式。Q.Xiao等(Biological Activities ofGlucagon-Like Peptide-1Analogues in Vitro and in Vivo,Biochem.,2001,40∶2860-2869)研究了Glu9替换为Asp9对(不含支链的)GLP-1与受体亲和力和活性的影响;CyrilSarrauste de Menthière等(Structural requirements of the N-terminal region ofGLP-1-[7-37]-NH2 for receptor interaction and cAMP production,Eur.J.Med.Chem.,2004,39:473-438)研究了Glu9替换为Asp9对(不含支链的)GLP-1-[7-37]-NH2与受体亲和力和活性的影响。
本发明旨在研究Glu9替换为Asp9同时含长效化支链修饰的GLP-1类多肽衍生物,力图开发成为延长半衰期同时保持多肽亲和力与活性的潜在药物,从而满足GLP-1类药物在代谢性疾病和更多领域应用的巨大临床需求。
发明内容
本发明提供了超长效GLP-1多肽衍生物或其盐,所述超长效GLP-1多肽衍生物为式(I)所示,主链中X2有且仅有一个其侧链的氨基连接式(II)所示支链的酰基并形成酰胺:
7H-Aib-X1-10G-T-F-T-S-D-V-S-S-Y-20L-E-G-Q-A-25A-X2-E-F-I-30A-W-L-V-X3-35G-R-G
(I)
其中,Aib为氨基异丁酸,X1选自D天冬氨酸,X2选自K赖氨酸,X3选自R精氨酸或K赖氨酸,X2有且仅有一个、其侧链的氨基连接式(II)所示支链的酰基并形成酰胺;B为十八烷二酸或二十烷二酸,其一端与谷氨酸的α氨基形成酰胺结构,另一端为羧酸结构。
为了便于识别和表述,氨基酸序列采用部分氨基酸左上角标注氨基酸位置的方式,该位置编号源自人体GLP-1(7-37)氨基酸序列位置并与其对应。
在本发明的一种实施方案中,所述超长效GLP-1多肽衍生物为下列式(III):
其中,式(III)对应多肽化合物(1):X1为D,X2为K,其氨基酸侧链ε氨基以酰胺键形式连接支链结构,X3为K,B为十八烷二酸,其一端与谷氨酸α氨基形成酰胺。
在本发明的一种实施方案中,所述超长效GLP-1多肽衍生物为下列式(IV)
其中,式(IV)对应多肽化合物(2):X1为D,X2为K,其氨基酸侧链ε氨基以酰胺键形式连接支链结构,X3为R,B为十八烷二酸,其一端与谷氨酸α氨基形成酰胺。
在本发明的一种实施方案中,所述超长效GLP-1多肽衍生物为下列式(V)
其中,式(V)对应多肽化合物(3):X1为D,X2为K,其氨基酸侧链ε氨基以酰胺键形式连接支链结构,X3为K,B为二十烷二酸,其一端与谷氨酸α氨基形成酰胺。
在本发明的一种实施方案中,所述超长效GLP-1多肽衍生物为下列式(VI)
其中,式(VI)对应多肽化合物(4):X1为D,X2为K,其氨基酸侧链ε氨基以酰胺键形式连接支链结构,X3为R,B为二十烷二酸,其一端与谷氨酸α氨基形成酰胺。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。在本发明的实施方案中,作为本发明的优选实施方式,所述的多肽化合物其中的氨基酸均优选为L型氨基酸。
文中表述的氨基酸均为国际标准单字母或三字母缩写。
另一方面,本发明提供了一种上述超长效GLP-1多肽衍生物的制备方法,所述的制备方法包括如下步骤A:
1)固相或液相法合成支链片段;
2)固相法合成肽链;
3)将支链片段与肽树脂偶联;
4)裂解除去保护基团与树脂挂载,得到超长效GLP-1多肽衍生物。
本发明提供了另一种上述超长效GLP-1多肽衍生物的制备方法,所述的制备方法包括如下步骤B:
1)固相法合成肽链;
2)固相法将支链各模块逐次与肽树脂偶联;
3)裂解除去保护基团与树脂挂载,得到超长效GLP-1多肽衍生物。
在一些实施例中,所述步骤A合成支链片段的方案如下所示:
按本发明支链片段结构顺序依次顺序或逆序连接,最后脱除需要与肽链结合的活性基团保护。该步骤可采用多肽固相合成的方式进行,也可采用液相合成的方式。
将苄酯单保护的3,6-二氧杂-辛二酸(结构见下)与Boc(叔丁氧羰基)单保护的3,6-二氧杂-1,8-辛二胺(结构见下)在弱有机碱条件下缩合偶联,TFA脱除Boc保护;将Fmoc-Glu-OtBu与前一步产物缩合偶联,Pip/DMF溶液或其它碱性溶液脱Fmoc保护;tBu基团单保护的十八烷二酸(或二十烷二酸)缩合偶联到E的氨基位置;最后采用钯碳催化作用下氢气水解脱除苄酯,暴露出需要与肽链结合的酰基。
在一些实施例中,所述步骤A合成主链的方案如下所示:
按本发明分子结构的氨基酸顺序将Fmoc保护氨基酸依次偶联到固相合成树脂上,Pip/DMF溶液或其它碱性溶液去保护Fmoc,循环直至主链氨基酸全部完成;其中最后一个氨基酸His的α氨基采用Boc基团保护;其中将待连接支链片段的Lys采用Alloc保护(可选地,采用原料Fmoc-Lys(Alloc)-OH);本发明采用CTC树脂、Wang树脂、HMPA-MBHA树脂、HMBA-AM树脂、羟甲基树脂、Rink Acid树脂等可构建羧酸型氨基酸的树脂进行固相合成。
在一些实施例中,所述步骤A支链与肽链偶联的方案如下:
脱肽树脂侧链保护;将支链片段与肽树脂偶联;(脱首位氨基酸Fmoc保护;)最后,裂解切割除去保护基团与树脂挂载,得到超长效GLP-1多肽衍生物。
采用四(三苯基膦)钯和PhSiH3脱去X2(Lys)的Alloc保护;将支链片段缩合偶联到肽树脂上;将Pip/DMF溶液或其它碱性溶液脱Fmoc保护;按比例(TFA∶EDT∶TIS∶H2O=95∶2∶2∶1)配制裂解液,将全保护肽树脂加入裂解液,从树脂上切割下来并脱除侧链。真空旋蒸除去TFA,将MTBE(甲基叔丁基醚)加入浓缩液析出白色固体即目标产物。
在一些实施例中,所述步骤B合成主链的方案与步骤A合成主链的方案相同。
在一些实施例中,所述步骤B固相法将支链各模块逐次与肽树脂偶联的方案如下:
该步骤采用多肽固相合成的方式进行,按本发明支链各模块结构顺序依次逆序连接到树脂上的多肽主链。先脱去X2(Lys)的侧链保护,连接单保护的3,6-二氧杂-辛二酸,再连接3,6-二氧杂-1,8-辛二胺,再连接Glu,最后连接十八烷二酸(或二十烷二酸)单叔丁酯完成整个支链的上载与合成。
采用四(三苯基膦)钯和PhSiH3脱去主肽链X2(Lys)的Alloc保护;缩合试剂预活化3,6-二氧杂-辛二酸,然后与主肽链反应偶联上载;然后加入Fmoc单保护的3,6-二氧杂-1,8-辛二胺缩合偶联;Pip/DMF溶液或其它碱性溶液脱去的Fmoc保护;缩合试剂预活化Fmoc-Glu-OtBu,再缩合偶联;Pip/DMF溶液或其它碱性溶液脱去Fmoc保护;tBu基团单保护的十八烷二酸(或二十烷二酸)缩合偶联到Glu的α氨基位置;至此完成整个支链的上载与合成。
在一些实施例中,步骤A和步骤B可阶段性实施构建本发明所述多肽化合物。
先按步骤A所述合成支链的一部分片段,然后按步骤B固相法将支链各模块逐次与肽树脂偶联。
采用3,6-二氧杂-辛二酸和Fmoc-3,6-二氧杂-1,8-辛二胺合成为片段;采用四(三苯基膦)钯和PhSiH3脱去主肽链X2(Lys)的Alloc保护;将前述片段与主肽链反应偶联上载;Pip/DMF溶液或其它碱性溶液脱去的Fmoc保护;缩合试剂预活化Fmoc-Glu-OtBu,再缩合偶联;Pip/DMF溶液或其它碱性溶液脱去Fmoc保护;tBu基团单保护的十八烷二酸(或二十烷二酸)缩合偶联到Glu的α氨基位置;至此完成整个支链的上载与合成。
可选地,进一步包括:
色谱纯化:进行多步反相色谱纯化或离子色谱纯化,最后转盐成含活性成分的水溶液;和冻干。
本发明公开的所述超长效G LP-1多肽衍生物的制备方法或方案采用的是化学合成的方式,但按现有技术手段设想,这类化合物可采用基因表达与重组并结合化学合成的半合成方式构建本发明所述超长效GLP-1多肽衍生物。所有这些可实施方案,均应包括在本发明的范围之内。
本发明前后文表述中所采用的一些化学基团或化学试剂或分子式的缩写均为本专业领域内常见和公知的缩写方式,不逐个列举其具体含义,但不影响其具体指向。
本发明公开了一种药物组合物,其包含本发明所述的化合物或其药学上可接受的盐为活性成分或主要活性成分,以及药学上可接受的载体。
构成本发明的一部分是药学上可接受的盐,适当的“药学上可接受的盐”包括本发明的游离型化合物、无机酸或有机酸反应形成的本发明化合物的常规无毒盐、无机碱或有机碱反应形成的本发明化合物的常规无毒盐。例如,包括得自无机酸例如盐酸、氢溴酸、硫酸、磷酸、硝酸等的盐,也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等的盐。又例如,包括得自无机碱例如钠、钾、钙、镁、锌、铁等的盐,也包括得自有机碱例如氨水、精氨酸、赖氨酸、瓜氨酸、组氨酸等的盐。
本发明的其中一个目标是根据本发明的超长效GLP-1多肽衍生物研究开发成为临床可用的药物制剂。该制剂可进一步包含缓冲剂、防腐剂、等渗剂、助溶剂、张度剂、螯合剂、稳定剂、抗氧化剂、表面活性剂、酸碱调节剂等。浓度通常为0.01mg/ml至50mg/ml,其中所述的制剂具有3.0至9.0的pH。
在本发明的一个实施方案中,药物制剂是含水制剂,即水溶液,通常是溶液、乳液或混悬液。
在另一个实施方案中,药物制剂是一种冻干制剂,在使用前加入溶剂和/或稀释剂至其中充分溶解后备用。
在另一个实施方案中,药物制剂是不需预先溶解的即用型干燥制剂,例如喷雾吸入冻干粉等。
在本发明的另一个实施方案中,药物制剂pH值的范围选择至关重要,会影响到GLP-1多肽衍生物的溶解性和稳定性,在某些特定条件下会产生多肽物理性聚集或吸附。在本发明的一个实施方案中,药物制剂的pH值为3.0~4.5。在本发明的一个实施方案中,药物制剂的pH值为7.0~8.0。在本发明的一个实施方案中,药物制剂的pH值为7.5~8.5。在本发明的另一个实施方案中,药物制剂的pH值为6.0~7.5。
在本发明的进一步实施方案中,缓冲剂选自磷酸氢二钠、乙酸钠等,防腐剂选自苯酚、邻甲酚、间甲酚、对甲酚等,等渗剂选自氯化钠类盐、糖或糖醇、氨基酸、丙二醇、甘露醇等,助溶剂选自甘露醇、丙二醇、PEG、甘油、吐温、乙醇等,张度剂选自氯化钠类盐、丙二醇、甘油、甘露醇等,螯合剂选自EDTA、柠檬酸盐等,稳定剂选自肌酐、甘氨酸、烟酰胺、PEG等,抗氧化剂选自亚硫酸氢钠、亚硫酸钠、半胱氨酸、甲硫氨酸等,表面活性剂选自聚山梨酯、甘油、甘露醇等,酸碱调节剂选自盐酸、磷酸、硫酸、氢氧化钠、氢氧化钾等。
其它成分可根据药物制剂的需要(例如长期稳定性)存在于本发明超长效GLP-1多肽衍生物的药物制剂中,包括乳化剂、金属离子、油质载体、蛋白质(如人血清白蛋白、明胶或蛋白质等)以及两性离子(例如精氨酸、甘氨酸、赖氨酸、组氨酸、甜菜碱和牛磺酸等)等和其它药用制剂添加剂。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质,代表性的载体包括水、油、脂质体等。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
第三方面,本发明提供了上述超长效GLP-1多肽衍生物的用途为GLP-1受体激动剂,所述的临床用途包括但不限于在制备治疗或预防下述至少一种疾病的药物中的应用,所述疾病包括II型糖尿病、糖耐量受损、I型糖尿病、肥胖、代谢综合征、非酒精性脂肪肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、神经退行性疾病如阿尔茨海默症(AD)、帕金森症(PD)等。
本发明所述超长效GLP-1多肽衍生物药学上可接受的游离化合物或盐,可用于糖尿病、肥胖相关疾病和糖尿病相关疾病、代谢综合征。糖尿病包括以因胰岛素分泌、胰岛素作用或其二者的缺陷引起的高血糖为特征的一组代谢疾病。根据病症机理将糖尿病分为I型糖尿病、II型糖尿病和妊娠糖尿病。
作为优选,还包括在制备治疗II型糖尿病药效延迟和/或预防II型糖尿病恶化的药物中的应用,以及改善II型糖尿病成人中血糖控制的方法、包括向有需要的患者施用有效量的上述多肽衍生物作为饮食和运动补充的应用。
作为优选,还包括在制备治疗II型糖尿病药效延迟和/或预防II型糖尿病恶化的药物中的应用。
作为优选,还包括在制备减少食物摄入量、减少β细胞凋亡、增加胰岛β细胞功能、增加β-细胞团和/或恢复葡萄糖对β-细胞的敏感性的药物中的应用。
本发明所述超长效GLP-1多肽衍生物药学上可接受的游离化合物或盐,还可用于治疗肥胖、胰岛素抵抗、糖耐量受损、前驱糖尿病、空腹血糖升高、II型糖尿病、高血压、血脂异常(或这些代谢风险因素的组合)、动脉粥样硬化、动脉硬化、冠心病、外周动脉疾病和卒中。这些都是可能与肥胖有关的病症。但是,本发明所述使用的化合物对这些病症的作用可通过对体重的作用来全面或部分地介导,或者可独立于所述作用。
在某些实施方案中,本发明所述GLP-1受体激动剂多肽衍生物药学上可接受的游离化合物或盐可在如肥胖相关炎症、肥胖相关胆囊疾病和肥胖诱发的睡眠呼吸暂停等肥胖相关疾病起到治疗作用。
本发明所述超长效GLP-1受体激动剂多肽衍生物药学上可接受的游离化合物或盐,对于与多个代谢相关的因素有关、发病机理复杂的NAFLD、NASH有积极预防与治疗意义。胰岛素抵抗及脂肪代谢紊乱构成了早期对肝脏的损伤,从而在肝脏细胞内形成脂肪堆积(NAFLD)。随着疾病的发展,机体免疫调节的形成,肝脏细胞产生炎症反应,继而推动形成纤维化,最终导致肝硬化等终末期肝病症状。而本发明所述GLP-1受体激动剂多肽衍生物能有效调节血糖水平参与代谢,对于NASH可全面或部分地介导,或者可独立于所述作用。
本发明所述GLP-1受体激动剂多肽衍生物药学上可接受的游离化合物或盐,对于与多个代谢相关的因素有关、发病机理复杂的神经退行性疾病如阿尔茨海默症(AD)、帕金森症(PD)等有积极预防与治疗意义。
作为优选,还包括降低脑内β淀粉样蛋白斑块沉淀、减少氧化应激引起的神经细胞损伤,调节神经突触的传递,增加突触的可塑性,刺激轴突绳子,影响长时程增强,从而改善记忆并提高认知水平。
作为优选,还包括激活大脑的GLP-1受体,增强多巴胺连接的功能,发挥抗炎作用,改善能量产生和开启细胞存活信号从而可改善运动性能。
第四方面,尽管现有技术条件下保守氨基酸之间的相互替换被认为是无差异的,本发明研究意外发现所述多肽衍生物因为支链修饰和氨基酸保守替换的差异而呈现出了比现有技术更好的非常显著的体内长效性。该技术优势有利于减少给药频次,提高临床病患的用药依从性。
第五方面,本发明研究发现所述多肽衍生物因为支链修饰和氨基酸替换的差异而具有相当好的GLP-1受体激动活性,达到了与索马鲁肽相似或更好的GLP-1受体激动效果和其它治疗受益。尽管现有技术条件下已有文献研究了Glu9替换为Asp9对不含支链的GLP-1或GLP-1-[7-37]-NH2与受体亲和力和活性的影响,但不同的研究团队对于Glu9替换为Asp9的研究结论不尽相同,又如文献描述的索马鲁肽的研究过程,支链修饰以后对活性的影响是未知的,些许变化可能导致活性变差或药代结果变差,本发明研究达到了与索马鲁肽相似或更好的GLP-1受体激动效果和其它治疗受益是令人惊奇的。
术语所述的“保守氨基酸替换”是指公知技术条件下芳香族氨基酸Phe、Trp、Tyr之间的相互置换;疏水性氨基酸Leu、Ile、Val之间的相互置换;极性氨基酸Gln、Asn之间的相互置换;碱性氨基酸Lys、Arg、His之间的相互置换;酸性氨基酸Asp、Glu之间的相互置换;羟基的氨基酸Ser、Thr之间的相互置换。
附图说明
图1表示的是SD大鼠单次给药血药浓度-时间曲线。
具体实施方式
实施例1:制备多肽化合物(2)
ESI-MS:[M+3H]1367.55,[M+4H]1025.96,[M+5H]821.01。
1)固相合成支链片段
将3,6-二氧杂-辛二酸缩合挂载到2-CTC树脂上,然后将Fmoc保护的3,6-二氧杂-1,8-辛二胺采用HATU/DIEA缩合偶联到树脂上;15%Pip/DMF溶液脱Fmoc保护;将Fmoc-Glu-OtBu采用HATU/DIEA缩合偶联到树脂;15%Pip/DMF溶液脱Fmoc保护;tBu基团单保护的十八烷二酸采用HATU/DIEA缩合偶联到树脂;30%TFE/DCM溶液将支链片段切割得到支链片段中间体。
2)固相法合成肽链
按分子结构的氨基酸顺序将Fmoc保护氨基酸依次偶联到固相合成树脂上,固相合成载体选用Rink Amide-AM树脂,15%Pip/DMF溶液去保护Fmoc,缩合试剂采用HATU/DIEA,循环直至肽链氨基酸全部完成;其中待连接支链片段的保护氨基酸为Fmoc-Lys(OAlloc)-OH,最后一个氨基酸His的α氨基采用Boc基团保护;
3)将支链片段与肽树脂偶联
采用四(三苯基膦)钯和PhSiH3脱去肽链上Lys的Alloc保护;将支链片段采用HATU/DIEA缩合偶联到肽树脂上;15%Pip/DMF溶液脱Fmoc保护;
4)裂解除去保护基团与树脂挂载
按比例(TFA∶TIS∶H2O=96∶3∶1)配制裂解液,将全保护肽树脂加入裂解液,从树脂上切割下来并脱除侧链。真空旋蒸除去TFA,将异丙醚加入浓缩液析出白色固体即目标产物;
5)色谱纯化与冻干
采用C8或C18柱进行多步反相色谱纯化,最后脱盐成游离型水溶液;冻干。
实施例2:制备多肽化合物(1)
ESI-MS:[M+3H]1358.23,[M+4H]1018.96,[M+5H]815.38
制备过程类似实施例1,固相合成肽链载体选用Wang树脂,20%Pip/DMF溶液脱Fmoc保护,缩合试剂采用PyBop/DIEA。支链采用tBu基团单保护的十八烷二酸。裂解时采用MTBE析晶。纯化采用离子色谱和反相色谱相结合的方式,最后转盐成醋酸水溶液冻干。
实施例3:制备多肽化合物(3)
ESI-MS:[M+3H]1367.54,[M+4H]1025.91。
1)液相法合成支链片段
将苄酯单保护的3,6-二氧杂-辛二酸与Boc(叔丁氧羰基)单保护的3,6-二氧杂-1,8-辛二胺在N-甲基吗啉条件下采用EDC+HOBt缩合偶联,33%TFA/DCM溶液脱除Boc保护;将Fmoc-Glu-OtBu与前一步产物采用DCC+HOSu缩合偶联,50%乙醇胺/DCM溶液脱Fmoc保护;tBu基团单保护的二十烷二酸缩合偶联到Glu的氨基位置;最后采用钯碳催化作用下氢气水解脱除苄酯;
2)固相法合成肽链
按分子结构的氨基酸顺序将Fmoc保护氨基酸依次偶联到固相合成树脂上,固相合成载体选用CTC树脂树脂,50%乙醇胺/DCM溶液去保护Fmoc,偶联试剂采用DIC+Cl-HOBt循环直至肽链氨基酸全部完成;其中待连接支链片段的Lys保护氨基酸采用原料Fmoc-Lys(Alloc)-OH,最后一个氨基酸His的α氨基采用Boc基团保护;
3)将支链片段与肽树脂偶联
采用四(三苯基膦)钯和PhSiH3脱去肽链上Lys的Alloc保护;将支链片段缩合采用DIC+C1-HOBt偶联到肽树脂上;50%乙醇胺/DCM溶液脱Fmoc保护;
4)裂解除去保护基团与树脂挂载
按比例(TFA∶TIS∶EDT∶H2O=96∶2∶1∶1)配制裂解液,将全保护肽树脂加入裂解液,从树脂上切割下来并脱除侧链。真空旋蒸除去TFA,将石油醚加入浓缩液析出白色固体即目标产物;
5)色谱纯化与冻干
纯化采用离子色谱和反相色谱相结合的方式,最后转盐成含钠的水溶液冻干。
实施例4:SD大鼠单次给药药代动力学实验
取SD大鼠,雌雄兼用,随机编号分组,每组动物数n≥6。
供试品溶液的配制方法:分别称取供试品多肽化合物(3)、多肽化合物(2)和索马鲁肽各0.2±0.02mg,用2.0mL注射用水充分溶解,得浓度为0.1mg/mL的供试品溶液,于给药前配制,2~8℃保存。
给药剂量为0.2mg/kg,给药体积为2.0mL/kg。经背部皮下注射给药。分别于给药前及给药后0.5、2.5、5.5、7.0、8.0、9.0、10.0、12.0、16.0、24.0、32.0、48.0h经颈静脉取血约0.3mL,置于放在冰浴上的含EDTA-K2抗凝管中,2h内以4℃、2600g离心10min,取血浆,并暂存于干冰中,14h内放入-60℃以下冰箱保存。用建立的LC-MS/MS法对血浆样品进行分析。
试验获得的原始数据,通过仪器软件拟合得到标准曲线方程和相关系数、计算各取样时间点血浆样本中的药物浓度和随行的质控样品浓度。
利用SPSS21.0对原始数据进行统计;药物浓度与时间数据用WinNonlin6.4软件按照非房室模型法进行代谢动力学参数计算。药代动力学实验结果见表1和图1。
表1:SD大鼠单次给药药代动力学实验结果
实验结果表明,本发明多肽化合物的半衰期与索马鲁肽相比非常显著地延长,其他主要药动学参数值也体现了该趋势。对于无法治愈的糖尿病或代谢性疾病需要长期用药的患者而言,半衰期延长对减少临床用药频次、提高病患用药依从性具有重要意义。同时由于GLP-1类药物可能有低血糖风险,本发明多肽化合物对比已上市的索马鲁肽,Cmax相近则可理解为低血糖风险较小,是药代数据较理想的GLP-1类潜在药物。
实施例5:ob/ob小鼠减肥降糖药效实验
ob/ob小鼠该品系带有ob基因(obese),肥胖小鼠为纯合子的自发突变,会导致单纯肥胖伴晚期糖尿病,是研究过度肥胖、内分泌以及免疫功能之间相互关系很好的经典模型动物。
40只ob/ob小鼠根据空腹体重,空腹血清TC、LDL,均衡随机分成4组,分别为模型对照组,多肽化合物(2)组,多肽化合物(3)组和索马鲁肽组,每组10只。另10只常规饲喂小鼠设为正常对照组(溶媒)。
模型对照组、正常对照组和索马鲁肽组每3天背部皮下注射给药1次,共给药8次(D0、D3、D6、D9、D12、D15、D18、D21)。多肽化合物(3)组,多肽化合物(2)组每4天背部皮下注射给药1次,共给药6次(D0、D4、D8、D12、D16、D20)。模型对照组和正常对照组给予生理盐水(0.15mL/20g),多肽化合物(3)组,多肽化合物(2)组和索马鲁肽组均按0.312mg/kg的剂量给药。
(1)体重:分组前禁食不禁水12h测定1次,根据体重和TC、LDL均衡随机分组。分组后自D0始,每天测定1次。同时观察进食量与饮水量。
(2)Lee’s指数:首次给药前和D23各测定1次体长。体长为鼻尖至***的最大直线长度。调整小鼠***使其身体呈舒展状态,用直尺刻度读出小鼠体长。
Lee’s指数=[体重(g)×103/体长(cm)]1/3。
(3)血液中葡萄糖(GLU)的测定:每3天测定一次。
(4)血液生化(TG、TC、LDL、HDL):分别在分组前,约D11和D23各测定一次。
(5)脂肪-体重系数:小鼠安乐死后,摘取腹部皮下脂肪、性腺周围脂肪,肩胛骨皮下脂肪并分别称重,计算脂肪-体重系数。
实验结果如下所述:
(1)体重
实验进行期间,模型对照组动物体重增长最快,在实验期间平均体重均显著高于正常对照组(p<0.01),实验终点时正常对照组动物平均增长约6.2g,模型对照组动物平均增长12.9g,多肽化合物(3)组动物平均增长4.5g,多肽化合物(2)组平均增长4.8g,索马鲁肽组动物平均增长5.8g。
从D1开始,多肽化合物(3)组、多肽化合物(2)组和索马鲁肽组动物体重出现下降,且进食量与饮水量减少(对比模型组与正常组)呈现出一定的规律性,即给药当天进食较少,随后逐渐恢复,这与药物激活GLP-1靶点减少饥饿感增强饱腹感的神经传导机制有关。实验期间(D1-D23)给药组体重增长缓慢,均显著低于模型对照组(p<0.01),多肽化合物(3)组、多肽化合物(2)组体重平均值略低于索马鲁肽组,且有统计学差异(p<0.05)。
(2)Lee’s指数
Lee’s指数是反应大鼠肥胖程度的有效指标,所有动物的Lee’s指数均增加,正常组动物增加最少。与模型对照组相比,各给药组动物Lee’s指数均略降低,有统计学差异。结果说明,多肽化合物(2)、多肽化合物(3)与阳性药索马鲁肽对于ob/ob小鼠的肥胖均能起到抑制作用,各药物的Lee’s指数控制能力接近。结果见表2:
表2:大鼠Lee′s指数结果
注:与模型对照组相比,*p<0.05,**p<0.01;与对应的阳性药相比,#p<0.05,##p<0.01
(3)随机血糖
实验期间,与模型对照组小鼠相比,D3-D23过程中多肽化合物(2)、多肽化合物(3)与阳性药索马鲁肽均有明显的降血糖作用。多肽化合物(2)和多肽化合物(3)组与阳性药索马鲁肽相比无显著差异。结果见表3(单位mmol/L):
表3:实验动物随机血糖变化结果
注:与模型对照组相比,*p<0.05,**p<0.01;与对应的阳性药相比,#p<0.05,##p<0.01。
(4)血液生化
①TC:给药前(D0)各组动物的初始TC水平较为接近。给药后,多肽化合物(2)组、多肽化合物(3)组和索马鲁肽组TC均低于模型对照组,相比于模型对照组,多肽化合物(2)组和多肽化合物(3)组能明显降低TC水平(p<0.05),且其降低TC的能力明显优于索马鲁肽组(p<0.05)。
②TG:给药前(D0)同品系小鼠TG水平较为接近。实验进行期间,模型对照组小鼠TG水平均高于正常对照组小鼠。给药后相比于模型对照组,多肽化合物(2)组、多肽化合物(3)组和索马鲁肽组可明显降低TG水平(p<0.05)。多肽化合物(2)组、多肽化合物(3)组从TG降低的数值看优于索马鲁肽组,但相互间无统计学差异。
③LDL:给药前(D0)同品系小鼠TG水平较为接近。给药后,相比于模型对照组,多肽化合物(2)、多肽化合物(3)和索马鲁肽均可明显降低LDL水平(p<0.01)。但多肽化合物(2)组、多肽化合物(3)组和索马鲁肽组之间无统计学差异。
④HDL:给药前(D0)同品系小鼠HDL水平较为接近。实验进行期间,模型对照组小鼠HDL水平均低于正常对照组小鼠。相比于模型对照组,给药后D11和D23,多肽化合物(2)组、多肽化合物(3)组与阳性药组均显著升高HDL水平,但多肽化合物(2)组、多肽化合物(3)组的HDL平均值比较阳性药组更低,相互间无统计学差异。
(5)脂肪-体重系数:
给药23天后解剖小鼠,分离不同部位脂肪,并根据公式(脂肪/体重×100)计算脂肪-体重系数。由结果可知,模型对照组小鼠各部位脂肪-体重系数均显著高于正常对照组小鼠。多肽化合物(2)、多肽化合物(3)均能显著降低ob/ob小鼠腹部皮下和性腺周围的脂肪,且效果与阳性药物索马鲁肽无明显差异。此外,药物对于肩胛骨皮下脂肪-体重系数无影响。结果见表4:
表4:脂肪-体重系数结果
注:与模型对照组相比,*p<0.05,料p<0.01;与阳性药相比,#p<0.05,##p<0.01。
综合分析以上实验数据,其结果表明,本发明的多肽衍生物具有相当好的GLP-1受体激动活性,达到了与阳性对照药索马鲁肽相似或更好的GLP-1受体激动效果,实现了ob/ob模型小鼠的减脂和降糖作用,并在血脂的某些指标方面有更好的治疗受益。
Claims (19)
1.一种超长效GLP-1多肽衍生物或其药学上可接受的盐,所述超长效GLP-1多肽衍生物或其盐由式(I)所示主链和式(II)所示支链组成,主链X2的侧链的氨基连接式(II)所示支链的酰基并形成酰胺:
7H-Aib-X1-10G-T-F-T-S-D-V-S-S-Y-20L-E-G-Q-A-25A-X2-E-F-I-30A-W-L-V-X3-35G-R-G
(I)
其中,Aib为氨基异丁酸,X1为D天冬氨酸,X2为K赖氨酸,X3选自R精氨酸或K赖氨酸,X2的侧链的氨基连接式(II)所示支链的酰基并形成酰胺;B为十八烷二酸或二十烷二酸,其一端与谷氨酸的α氨基形成酰胺结构,另一端为羧酸结构。
2.根据权利要求1所述的多肽衍生物或其药学上可接受的盐,其特征在于多肽链9号位为Asp,同时主链有且仅有X2位Lys其侧链ε-氨基以酰胺键形式连接式(II)所示的含长脂肪酸、PEG连接子和谷氨酸修饰的支链。
3.根据权利要求1所述的超长效GLP-1衍生物或其药学上可接受的盐,其特征在于,所述超长效GLP-1衍生物如式(III)所示:
4.根据权利要求1所述的超长效GLP-1衍生物或其药学上可接受的盐,其特征在于,所述超长效GLP-1衍生物如式(IV)所示:
5.根据权利要求1所述的超长效GLP-1衍生物或其药学上可接受的盐,其特征在于,所述超长效GLP-1衍生物如式(V)所示:
6.根据权利要求1所述的超长效GLP-1衍生物或其药学上可接受的盐,其特征在于,所述超长效GLP-1衍生物如式(VI)所示:
7.根据权利要求1所述的超长效GLP-1衍生物或其药学上可接受的盐,其特征在于多肽化合物中的氨基酸均为L型氨基酸。
8.权利要求1至6中任一项所述超长效GLP-1多肽衍生物的制备方法,其特征在于,包括如下步骤A:
1)固相或液相法合成支链片段;
2)固相法合成肽链;
3)将支链片段与肽树脂偶联;
4)裂解除去保护基团与树脂挂载,得到超长效GLP-1多肽衍生物;
或包括如下步骤B:
1)固相法合成肽链;
2)固相法将支链各模块逐次与肽树脂偶联;
3)裂解除去保护基团与树脂挂载,得到超长效GLP-1多肽衍生物。
9.一种药物组合物,其特征在于包含权利要求1至6中任一项所述超长效GLP-1衍生物或其药学上可接受的盐和可药用制剂。
10.根据权利要求9所述的药物组合物,其特征在于,所述的药学上可接受的盐为所述超长效GLP-1衍生物的游离型化合物、其与无机酸或有机酸反应形成的常规无毒盐、其与无机碱或有机碱反应形成的常规无毒盐,所述无机酸为盐酸、氢溴酸、硫酸、磷酸、硝酸,所述有机酸为乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸,所述无机碱为钠、钾、钙、镁、锌、铁,所述有机碱为氨水、精氨酸、赖氨酸、瓜氨酸、组氨酸。
11.根据权利要求9所述的药物组合物,其特征在于,可药用制剂为含水制剂、或冻干制剂或即用型干燥制剂,制剂含有缓冲剂、防腐剂、等渗剂、助溶剂、张度剂、螯合剂、稳定剂、抗氧化剂、表面活性剂、酸碱调节剂、乳化剂、金属离子、油质载体以及两性离子和其它药用制剂添加剂中的任意一种或多种。
12.根据权利要求11所述药物组合物,其特征在于,可药用制剂浓度为0.01mg/ml至50mg/ml,且具有3.0至9.0的pH值。
13.权利要求1至6中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求9至12中任一项所述药物组合物在制备治疗和/或预防下列至少一种疾病的药物中的应用:II型糖尿病、糖耐量受损、I型糖尿病、肥胖、代谢综合征。
14.权利要求1至6中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求9至12中任一项所述药物组合物在制备治疗II型糖尿病药效延迟和/或预防II型糖尿病恶化的药物中的应用。
15.权利要求1至6中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求9至12中任一项所述药物组合物在制备治疗和/或预防下列至少一种与肥胖相关疾病的药物中的应用:肥胖、胰岛素抵抗、糖耐量受损、前驱糖尿病、空腹血糖升高、Ⅱ型糖尿病、高血压、血脂异常、动脉粥样硬化、动脉硬化、冠心病、外周动脉疾病和卒中。
16.根据权利要求15所述的应用,其特征在于权利要求1至6中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求9至12中任一项所述药物组合物在制备治疗肥胖相关炎症、肥胖诱发的睡眠呼吸暂停的药物中的应用。
17.权利要求1至6中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求9至12中任一项所述药物组合物在制备治疗和/或预防下列至少一种疾病的药物中的应用:非酒精性脂肪肝炎(NASH)、非酒精性脂肪肝病(NAFLD)。
18.根据权利要求17所述的应用,其特征在于权利要求1至9中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求11所述药物组合物在制备治疗胰岛素抵抗、脂肪代谢紊乱的药物中的应用。
19.权利要求1至6中任一项所述超长效GLP-1多肽衍生物或其药学上可接受的盐或权利要求9至12中任一项所述药物组合物在制备治疗和/或预防下列至少一种疾病的药物中的应用:阿尔茨海默症(AD)、帕金森症(PD)。
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