CN104144704A - Glp-1受体激动剂肽胃泌素缀合物 - Google Patents
Glp-1受体激动剂肽胃泌素缀合物 Download PDFInfo
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- CN104144704A CN104144704A CN201280060332.8A CN201280060332A CN104144704A CN 104144704 A CN104144704 A CN 104144704A CN 201280060332 A CN201280060332 A CN 201280060332A CN 104144704 A CN104144704 A CN 104144704A
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- 8ado
- solvate
- glu
- officinal salt
- peptide
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Abstract
本发明特别地涉及某些肽缀合物,以及所述缀合物在治疗多种疾病或病症(包括糖尿病(1型和/或2型)和糖尿病相关疾病或病症)中的用途。
Description
技术领域
本发明特别地涉及某些肽缀合物,以及这些缀合物在治疗和/或预防多种疾病或病症(包括糖尿病(1型和/或2型)和糖尿病相关的疾病或病症)中的用途。
背景技术
糖尿病(特别是1型和2型糖尿病)连同肥胖(其被认为是发生2型糖尿病的主要致病因素)构成世界范围内主要且甚至增长的健康问题。可作为糖尿病之结果而发生的疾病或病症包括心血管和外周血管疾病、微血管和大血管并发症、卒中以及可能的某些形式的癌症。
糖尿病的特征在于血糖水平的生理调节缺陷。可导致糖尿病的根本条件是胰β细胞量及功能的降低或损失,伴随内源性胰岛素产生的附带降低或损失和/或胰岛素抗性(对胰岛素的敏感性降低),即内源性胰岛素对血糖水平之适当调节能力的降低或损失。
许多降低血糖水平的激素响应肠内营养物之存在和吸收而由胃肠粘膜分泌。这些激素包括胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)、葡萄糖依赖性促胰岛素肽(glucose-dependent insulinotropicpeptide,GIP)、胃泌素(gastrin)和胰泌素(secretin)。
GLP-1[参见例如Diabetologia35:701-711(1992)]由胰高血糖素原(一种180个氨基酸的肽)的组织加工而产生[参见例如Drucker,Diabetes47:159-169(1998)]。胰高血糖素原的整个序列含有胰高血糖素的29个氨基酸序列、GLP-1的36或37个氨基酸序列和胰高血糖素样肽-2(GLP-2;一种肠营养肽(intestinotrophic peptide))的34个氨基酸序列。
所谓的毒蜥外泌肽(exendin)(其构成另一组降低血糖水平的肽)与GLP-1(7-36)有一定的序列类似性(53%)[参见例如Goke等,J.Biol.Chem.268:19650-19655(1993)]。毒蜥外泌肽见于毒蜥科(Helodermatidae)物种(珠蜥(beaded lizard))的唾液中。毒蜥外泌肽-3存在于珠毒蜥(Heloderma horridum)(墨西哥珠蜥(Mexican beadedlizard))的唾液中,而毒蜥外泌肽-4存在于钝尾毒蜥(Helodermasuspectum)(希拉毒蜥(Gila monster))的唾液中。毒蜥外泌肽-4的氨基酸序列(其在位置2和位置3处不同于毒蜥外泌肽-3的氨基酸序列)为HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2。
已报道毒蜥外泌肽-4是一种对于经分离大鼠胰岛素瘤细胞强大的GLP-1受体激动剂[Goke等,在上述引文中]。WO99/07404公开了全身施用的毒蜥外泌肽-4使得糖尿病db/db小鼠内的血糖糖水平降低40%,且也已报道每日一次腹膜内注射毒蜥外泌肽-4对糖尿病ob/ob小鼠的持久血糖降低作用[Grieg等,Diabetologia42:45-50(1999)]。
US5,424,286和WO98/05351公开了毒蜥外泌肽-3、毒蜥外泌肽-4和毒蜥外泌肽激动剂可用于治疗糖尿病、用于降低胃运动以及延迟胃排空且用于预防高血糖,且WO98/30231另外公开了它们可用于降低食物摄取。
肽激素胃泌素由胃黏膜内的细胞以及十二指肠内的G细胞分泌,且该激素对人的主要生理学作用是刺激胃酸(即HCl)分泌且帮助胃运动。有显示胃泌素可对胰岛(islet)新生发挥作用,即刺激胰岛中分泌胰岛素之β细胞的生长[参见例如Korc,M.,J.Clin.Invest.,92:1113-1114(1993);Rooman等,Diabetes51:686-690(2002)],并因此有助于血糖的调节。
胃泌素与另一胃肠肽激素胆囊收缩素(CCK)共享受体。受体CCK-AR和CCK-B R对胃泌素及CCK变体具有不同亲和力。CCK-AR(或CCKR1)主要用作硫酸化之CCK的受体,而CCK-B R(或CCK R2)同等良好地结合CCK与胃泌素二者。CCK-B R由于胃泌素在血浆中与CCK相比之较高水平而被认为是“胃泌素受体”[Foucaud等,Reg.Peptides145:17-23(2008)]。
CCK-B R在结合配体后可起始若干细胞内途径,其被认为是CCK多样的生理作用的原因。CCK-B R下游的关键途径为MAPK(mitogenactivated protein kinase,丝裂原活化蛋白激酶)或ERK(extra-cellularregulated kinase,细胞外调节激酶)途径,其也由若干种生长激素活化。由于CCK-B R在胰中表达,因此胃泌素能够促成此组织中的细胞增殖和胰岛再生。
在人中,胃泌素主要以三种形式出现,即胃泌素34、胃泌素17和胃泌素14(参考所关注序列中的氨基酸总数)。也已鉴定了胃泌素6。较短形式由C端酰胺化之胃泌素34的切割产生;因此胃泌素17由胃泌素34的最后17个C端残基组成(对应于前胃泌素(55-71)),胃泌素14由胃泌素34的最后14个C端残基组成(对应于前胃泌素(58-71))且胃泌素6仅由胃泌素34的最后6个C端残基组成(对应于前胃泌素(66-71))。在人胃泌素17中,N端氨基酸残基为焦谷氨酸(PyroGlu)残基。经酰胺化的C端6个氨基酸为胃泌素的关键受体结合残基。
发明概述
现已发现,包含两个共价偶联或连接之肽部分的某些缀合物与所关注的两种单独肽之组合的治疗活性相比,在治疗例如糖尿病(1型和/或2型糖尿病)或多种其他糖尿病相关疾病或病症时可显示出出乎意料的高治疗活性。
在一个广泛的方面中,本发明提供GLP-1受体激动剂与胃泌素(特别为在胃泌素17之位置15处(对应于胃泌素6的位置4)具有选自Leu、Nle、Phe及Thr之替换的胃泌素)的肽缀合物。更特别地,本发明提供毒蜥外泌肽-4与胃泌素的肽缀合物。
在一些实施方案中,本发明因此提供具有式I的肽缀合物或者其可药用盐或溶剂合物,
R1-Za-La-Ya-R2 (I)
其中
R1为H、C1-4烷基、乙酰基、甲酰基、苯甲酰基或三氟乙酰基;
R2为OH或NH2;且
Za为具有式Ia的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-Z13-Z14-Glu-Z16-Glu-Ala-Val-Z20-Leu-Phe-Ile-Z24-Z25-Leu-Z27-Z28(Ia)
其中
Z9选自Asp和Glu;
Z12选自Lys、Arg和Orn;
Z13选自Gln和Tyr;
Z14选自Met和Leu;
Z16选自Glu、Cys、Arg、Orn和Lys;
Z20选自Arg、Lys和Orn;
Z24选自Lys、Arg、Orn和Glu;
Z25选自Trp、Lys、Cys和Phe;
Z27选自Lys、Arg和Orn;且
Z28选自Asn和Asp或不存在;
La为具有式Ib的肽序列
L1-L2-L3-L4 (Ib)
其中
L1选自Orn、8Ado、Cys、Lys和Gln或不存在;
L2选自Orn、8Ado、Cys、Lys和Gln或不存在;
L3选自Orn、8Ado、Cys、Lys和Gln或不存在;且
L4选自Orn、8Ado、Cys、Lys和Gln或不存在;且
Ya为具有式Ic的肽序列:
Y12-Y13-Y14-Y15-Asp-Y17 (Ic)
其中
Y12选自Tyr和Ala或不存在;
Y13选自Gly和Ala或不存在;
Y14选自Trp、1Nal和Phe;
Y15选自Met、Leu、Nle、Thr和Phe;且
Y17选自Phe和3-(3-吡啶基)-丙氨酸;
其中式Ia及Ib中Lys、Orn或Cys中的至少一个进一步与亲脂性和/或生物素基(biotinylic)取代基缀合和/或聚乙二醇化。
在另一些实施方案中,本发明提供式I的肽缀合物或者其可药用盐或溶剂合物,其中
Za为具有式IIa的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Lys-Z13-Z14-Glu-Z16-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28 (IIa)
其中
Z9选自Glu和Asp;
Z13选自Gin和Tyr;
Z14选自Met和Leu;
Z16选自Glu、Cys和Lys;
Z25选自Lys、Phe、Cys和Trp;且
Z28选自Asn和Asp或不存在;
La为具有如上所述式Ib的肽序列;且
Ya为具有式IIc的肽序列
Tyr-Gly-Trp-Y15-Asp-Phe (IIc)
其中
Y15选自Leu和Thr;且
其中式IIa的位置Z16和Z25中的Lys残基中至少一个进一步与亲脂性和/或生物素基取代基(biotinylic substituent)缀合和/或聚乙二醇化。
在一些特定实施方案中,本发明涉及具有下式的肽缀合物或者其可药用盐或溶剂合物:
H-HGEGTFTSDLSKQLEEEAVRLFIEWLKN-8Ado-K(十六烷酰基-异Glu)-8Ado-YGWLDF-NH2(化合物1)
H-HGEGTFTSDLSKQLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物2)
H-HGEGTFTSDLSKQLE-K(十六烷酰基-异Glu)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物3)
H-HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-C(生物素-Mal)-8Ado-YGWLDF-NH2(化合物4)
H-HGEGTFTSDLSKQLEEEAVRLFIE-C(生物素-Mal)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物5)
H-HGEGTFTSDLSKQLE-C(生物素-Mal)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物6)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-8Ado-YGWLDF-NH2(化合物7)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-QQYGWLDF-NH2(化合物8)
A 。
在另一些实施方案中,本发明提供具有式III的肽缀合物或者其可药用盐或溶剂合物,
R1-Zb-Lb-Yb-R2 (III)
其中
R1为H、C1-4烷基、乙酰基、甲酰基、苯甲酰基或三氟乙酰基;
R2为OH或NH2;且
Zb为具有式IIIa的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28 (IIIa)
其中
Z25选自Phe和Trp;且
Z28选自Asn和Asp或不存在;
Lb为具有式IIIb的肽序列
L5-L6-L7-L8 (IIIb)
其中
L5选自8Ado、8Aoc、Ala、Gly和Gln或不存在;
L6选自8Ado、8Aoc、Ala、Gly和Gln或不存在;
L7选自8Ado、8Aoc、Ala、Gly和Gln或不存在;且
L8选自8Ado、8Aoc、Ala、Gly和Gln或不存在;且
Yb为具有式IIIc的肽序列
Y10-Y11-Tyr-Gly-Trp-Y15-Asp-Phe(IIIc)
其中
Y10为Glu或不存在;
Y11为Ala或不存在;且
Y15选自Leu和Thr;
前提为式III不为
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKYGWLDF-NH2;和
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-YGWLDF-NH2。
在另一些实施方案中,本发明提供式III的肽缀合物或者其可药用盐或溶剂合物,其中
Zb为具有式IVa的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Asn(IVa)
其中
Z25选自Lys、Phe和Trp;且
Lb为具有如上所述式IIIb的肽序列;
Yb为具有式IVc的肽序列
Tyr-Gly-Trp-Y15-Asp-Phe(IVc)
其中
Y15选自Leu和Thr。
在一些特定实施方案中,本发明涉及具有下式的肽缀合物或者其可药用盐或溶剂合物:
H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF-NH2(化合物9)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF-NH2(化合物10)
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-QQYGWLDF-NH2(化合物11)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH2(化合物12)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF-NH2(化合物13)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF-NH2(化合物14)
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Aoc-YGWLDF-NH2(化合物15)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF-NH2(化合物16)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH2(化合物17)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWLDF-NH2(化合物18)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKD-8Ado-8Ado-YGWLDF-NH2(化合物19)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH2(化合物20)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF-NH2(化合物21)
H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH2(化合物22)
H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH2(化合物23)。
在一些特定实施方案中,本发明的肽缀合物可通过标准合成方法,通过使用重组表达系统或通过任何其他合适的方法来制造。因此,缀合物可由多种方式来合成,包括例如包括以下的方法:
(a)通过标准固相或液相方法逐步或通过片段组装(fragment assembly)合成肽缀合物,并分离及纯化最终肽缀合物产物;
(b)在宿主细胞中表达编码肽缀合物的核酸构建体并自宿主细胞培养物回收表达产物;或
(c)影响编码肽缀合物之核酸构建体的无细胞体外表达,并回收表达产物;或通过方法(a)、(b)或(c)之任意组合获得肽缀合物的片段,随后连接这些片段以获得肽缀合物,并回收肽缀合物。
本发明的另一些实施方案为治疗多种病状、疾病或病症(包括糖尿病(1型和2型)和多种糖尿病相关病状、疾病或病症)的方法。这些实施方案包括施用本发明的肽缀合物(呈游离形式或者其可药用盐或溶剂合物形式)以及包含本发明之肽缀合物或者其可药用盐或溶剂合物的药物组合物。
在一些实施方案中,本发明的肽缀合物可用作用于治疗以下疾病的药剂:胰岛素抗性、葡萄糖不耐受、前驱糖尿病、代谢综合征、空腹葡萄糖水平升高、与血糖水平升高相关的疾病状态、高血糖、1型和/或2型糖尿病、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病、肾衰竭、高血压和/或血脂异常(或这些代谢与心血管风险因素的组合)、动脉粥样硬化、动脉硬化、大血管疾病、微血管疾病、冠心病、外周动脉疾病和卒中。其也可用于预防体重增长、促进体重减轻、降低体重过重和/或治疗肥胖(例如通过控制食欲、进食、食物摄取、热量摄取和/或能量消耗),包括病态肥胖以及相关疾病、病症及健康状况,包括但不限于肥胖相关性炎症、肥胖相关性胆囊疾病和肥胖诱发的睡眠呼吸暂停。本发明的肽缀合物对这些病状的作用可通过对体重的作用而整体或部分介导,或可不依赖于这些。
本发明的另一些实施方案为预防多种病状、疾病或病症(包括糖尿病(1型和2型)和多种糖尿病相关病状、疾病或病症)的方法。这些实施方案包括施用本发明的肽缀合物(呈游离形式或者其可药用盐或溶剂合物形式)以及包含本发明之肽缀合物或者其可药用盐或溶剂合物的药物组合物。
在一些实施方案中,本发明的肽缀合物可用作用于预防以下疾病的药剂:胰岛素抗性、葡萄糖不耐受、前驱糖尿病、代谢综合征、空腹葡萄糖水平升高、与血糖水平升高相关的疾病状态、高血糖、1型和/或2型糖尿病、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病、肾衰竭、高血压和/或血脂异常(或这些代谢与心血管风险因素的组合)、动脉粥样硬化、动脉硬化、大血管疾病、微血管疾病、冠心病、外周动脉疾病和卒中。其也可用于预防体重增长、促进体重减轻、降低体重过重和/或治疗肥胖(例如通过控制食欲、进食、食物摄取、热量摄取和/或能量消耗),包括病态肥胖以及相关疾病、病症及健康状况,包括但不限于肥胖相关性炎症、肥胖相关性胆囊疾病和肥胖诱发的睡眠呼吸暂停。本发明之肽缀合物对这些病状的作用可通过对体重的作用而整体或部分介导,或可不依赖于这些。
本发明的另一些方面将通过以下公开内容而变得明显。
附图说明
图1.处理3周后的空腹血糖糖水平
每天一次皮下(SC)施用载剂(vehichle)、利拉鲁肽(liraglutide)(每天100nmol/kg)及化合物18(每天30和100nmol/kg)对db/db小鼠处理3周后对空腹血糖水平的影响。数据以带有SEM的平均值给出。
统计学:通过单因素方差分析(1-way ANOVA),继之由Bonferroni’sMC检验,相对于载剂或相对于利拉鲁肽来比较数据:***p<0.001相对于载剂,##p<0.01相对于利拉鲁肽。
图2.处理4周,继之1周药物假期后的空腹血糖水平
对db/db小鼠处理4周、继之1周药物假期(载剂处理)后,每天一次皮下施用载剂、利拉鲁肽(每天100nmol/kg)及化合物18(每天30和100nmol/kg)对空腹血糖水平的影响。数据以带有SEM的平均值给出。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:**p<0.01相对于载剂,#p<0.05相对于利拉鲁肽。
图3.处理3周后之OGTT,AUC
对db/db小鼠处理3周后,每天一次皮下施用载剂、利拉鲁肽(每天100nmol/kg)及化合物18(每天30和100nmol/kg)对葡萄糖耐量的影响。数据表示为带有SEM的曲线下面积(area under the curve,AUC)。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:***p<0.001相对于载剂,###p<0.001相对于利拉鲁肽。
图4.处理4周+1周药物假期后的OGTT,AUC
对db/db小鼠处理4周、继之1周药物假期(载剂处理)后,每天一次皮下施用载剂、利拉鲁肽(每天100nmol/kg)及化合物18(每天30和100nmol/kg)对葡萄糖耐量的影响。数据表示为带有SEM的曲线下面积(AUC)。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:*p<0.05、***p<0.001相对于载剂,###p<0.001相对于利拉鲁肽。
图5.处理4周后的Δ体重
对db/db小鼠处理4周后,每天一次皮下施用载剂、利拉鲁肽(每天100nmol/kg)及化合物18(每天30和100nmol/kg)对Δ(结束-开始)体重的影响。数据以带有SEM的平均值给出。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:***p<0.001相对于载剂,##p<0.01相对于利拉鲁肽。
图6.处理5周后的空腹血糖水平
对ZDF大鼠处理5周后,每天两次皮下施用载剂、利拉鲁肽(每天2×40nmol/kg)及化合物18(每天2×10和2×40nmol/kg)对空腹血糖水平的影响。数据以带有SEM的平均值给出。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:**p<0.01、***p<0.001相对于载剂,###p<0.001相对于利拉鲁肽。
图7.处理5周后的OGTT,AUC
对db/db小鼠处理5周后,每天一次皮下施用载剂、利拉鲁肽(每天2×40nmol/kg)及化合物18(每天2×10及2×40nmol/kg)对葡萄糖耐量的影响。数据表示为带有SEM的曲线下面积(AUC)。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:***p<0.001相对于载剂,###p<0.001相对于利拉鲁肽。
图8.处理6周后的HbA1c水平
对ZDF大鼠处理6周后,每天两次皮下施用载剂、利拉鲁肽(每天2×40nmol/kg)及化合物18(每天2×10和2×40nmol/kg)对HbA1c水平的影响。数据以带有SEM的平均值给出。
统计学:通过单因素方差分析,继之由Bonferroni’s MC检验,相对于载剂或相对于利拉鲁肽来比较数据:***p<0.001相对于载剂,#p<0.05相对于利拉鲁肽。
发明详述
如上文所示,本发明的一个方面涉及具有下式的肽缀合物:
H-HGEGTFTSDLSKQLEEEAVRLFIEWLKN-8Ado-K(十六烷酰基-异Glu)-8Ado-YGWLDF-NH2(化合物1)
H-HGEGTFTSDLSKQLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物2)
H-HGEGTFTSDLSKQLE-K(十六烷酰基-异Glu)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物3)
H-HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-C(生物素-Mal)-8Ado-YGWLDF-NH2(化合物4)
H-HGEGTFTSDLSKQLEEEAVRLFIE-C(生物素-Mal)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物5)
H-HGEGTFTSDLSKQLE-C(生物素-Mal)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物6)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-8Ado-YGWLDF-NH2(化合物7)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-QQYGWLDF-NH2(化合物8) 。
此外,在另一个方面中,本发明涉及具有F式的肽缀合物:
H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF-NH2(化合物9)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF-NH2(化合物10)
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-QQYGWLDF-NH2(化合物11)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH2(化合物12)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF-NH2(化合物13)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF-NH2(化合物14)
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Aoc-YGWLDF-NH2(化合物15)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF-NH2(化合物16)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH2(化合物17)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWLDF-NH2(化合物18)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKD-8Ado-8Ado-YGWLDF-NH2(化合物19)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH2(化合物20)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGVVTDF-NH2(化合物21)
H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH2(化合物22)
H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH2(化合物23)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKEAYGWLDF-NH2(化合物24)
A 。
在另一个方面中,本发明涉及具有下式的肽缀合物:
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六烷酰基-异Glu)-YGWLDF-NH2(化合物25)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六烷酰基-异Glu)-WLDF-NH2(化合物26)
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKNYGWLDF-NH2(化合物27)
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKNWLDF-NH2(化合物28)
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六烷酰基-异Glu)-YGWLDF-NH2(化合物29)
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六烷酰基-异Glu)-WLDF-NH2(化合物30)
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKYGWLDF-NH2(化合物31)
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKWLDF-NH2(化合物32)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-YGWLDF-NH2(化合物33)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKQQYGWLDF-NH2(化合物34)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-Orn-Orn-YGWLDF-NH2(化合物35)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKNYGWLDF-NH2(化合物36)
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKDYGWLDF-NH2(化合物37)。
在另一个方面中,本发明涉及具有下式的肽缀合物或者其可药用的盐或溶剂合物:
H-HGEGTFTSDLSKQLEEEAVRLFIEC(PEG5K)LKN-8Ado-8Ado-YGWLDF-NH2(化合物38)
H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG10K)LK-8Ado-8Ado-YGWLDF-NH2(化合物39)
H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG20K)LK-8Ado-8Ado-YGWLDF-NH2(化合物40)
H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG40K)LK-8Ado-8Ado-YGWLDF-NH2(化合物41)
H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNYGWTDF-OH(化合物42)
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWTDF-NH2(化合物43)
。
缩写8Ado、8Aoc、十六酰基、异Glu、Orn以及生物素-Mal分别表示以下非天然氨基酸部分:
8Ado(或Peg3):-NH-CH2-CH2-O-CH2-CH2-O-CH2-C(O)-(衍生自8-氨基-3,6-二氧杂辛酸);
8Aoc:-NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-C(O)-(衍生自8-氨基辛酸)l;
十六酰基:CH3-(CH2)14-C(O)-;
异Glu:-NH-CH(COOH)-CH2-CH2-C(O)-;
Orn:鸟氨酸;且
生物素-Mal:生物素-马来酰亚胺。
关于本发明肽缀合物中接头部分的取向,接头部分-8Ado-8Ado-例如表示化学部分
-NH-CH2-CH2-O-CH2-CH2-O-CH2-C(O)-NH-CH2-CH2-O-CH2-CH2-O-CH2-C(O)-
,
位于所关注接头部分末端的-NH-....部分共价连接至所关注肽缀合物的GLP-1激动剂(例如毒蜥外泌肽-4衍生的)部分,且位于所关注接头部分右侧之....-C(O)-部分连接至所关注肽缀合物的胃泌素衍生部分。
在上文所列之本发明的肽缀合物中,应了解,毒蜥外泌肽-4(1-28)肽序列部分衍生自钝尾毒蜥毒蜥外泌肽-4序列的序列或为其类似物。
本发明上下文中的术语”毒蜥外泌肽-4类似物”被定义为衍生自天然(native)毒蜥外泌肽-4序列之任何替换、截断、缺失、添加或缀合的肽序列。这包括但不限于本发明的替换。
同样地,缀合物中的[Leu4]胃泌素6部分合成地衍生自人胃泌素。
也同样地,缀合物中的[Leu15]胃泌素17部分合成地衍生自人胃泌素。
上述肽缀合物1-41的每一个各自地(即化合物1或化合物2或化合物3...等(直至化合物41)或者其可药用盐或溶剂合物)构成本发明的另一个别方面。
在本发明上下文中,除非氨基酸以其全名提及(例如丙氨酸、精氨酸等),否则其由其常规的三个字母和/或单个字母缩写表示(例如Ala或A表示丙氨酸、Arg或R表示精氨酸,等)。
本发明上下文中的术语“肽缀合物”指其中第一肽部分直接或经由连接(即桥接或间隔)化学部分通过共价化学键键合与第二肽部分连接(即偶联或连接)的分子。
在本发明的肽缀合物中,毒蜥外泌肽-4或者Z(Za或Zb)与天然钝尾毒蜥毒蜥外泌肽-4可具有至少75%同一性,例如至少80%、85%、90%、95%、96%、97%、98%、99%或100%的同一性。
在本发明的肽缀合物中,胃泌素或Y(Ya或Yb)与天然人胃泌素17和/或胃泌素6可具有至少70%同一性,例如当可能时至少75%、80%、83%、85%、90%、94%、95%、96%、97%、98%、99%或100%的同一性。
在一些实施方案中,本发明的多肽可包含以下编号化合物任意一种中所列的氨基酸序列:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40和41或可能时其与一个或更多个所记载序列具有至少约80%、85%、90%、95%、97%、98%、99%或99.5%同一性的功能性片段或变体。氨基酸替换可以是例如保守替换。
如本文所用的术语“保守替换”表示一个或更多个氨基酸由另一生物学类似残基替代。实例包括具有类似特征之氨基酸残基的替换,例如小氨基酸、酸性氨基酸、极性氨基酸、碱性氨基酸、疏水性氨基酸和芳族氨基酸。例如,在本发明的一个优选实施方案中,Met残基由正亮氨酸(norleucine,Nle)替换,Nle对于Met而言为生物电子等排体(bioisostere),但与Met相反不易于氧化。以通常不见于内源性哺乳动物肽和蛋白质中之残基进行的保守替换的另一个实例为以例如鸟氨酸、刀豆氨酸、胺基乙基半胱氨酸或其他碱性氨基酸保守替换Arg或Lys。关于肽和蛋白质中表型沉默替换的进一步信息参见例如Bowie等,Science247,1306-1310,1990。氨基酸的保守替换由物理化学性质来分组。I:中性、亲水性,II:酸及酰胺,III:碱性,IV:疏水性,V:芳族、庞大氨基酸(bulkyamino acid)。
I | II | III | IV | V |
A | N | H | M | F |
S | D | R | L | Y |
T | E | K | I | W |
P | Q | V | ||
G | C |
在一些实施方案中,本发明的多肽可包含其功能性片段或变体,所述功能性片段或变体与一个或更多个所记载的序列相比具有至多20、15、10、9、8、7、6、5、4、3、2或1个氨基酸替换。本发明的多肽可另外具有或不具有信号序列。
在一些实施方案中,本发明多肽的一个或更多个半胱氨酸可由其他残基(例如丝氨酸)替换。
在一些实施方案中,本发明的多肽与以下编号化合物任意一种共有至少99%的氨基酸序列同一性:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40和41。
本发明上下文中的术语“可药用盐”(本发明肽缀合物之可药用盐)旨在表示对所关注盐施用之患者或对象无害的盐。其可合适地为例如在酸加成盐和碱盐间选择的盐。酸加成盐的实例包括氯化物盐、柠檬酸盐和乙酸盐。碱盐的实例包括阳离子选自碱金属阳离子(例如钠或钾离子)、碱土金属阳离子(例如钙或镁离子)以及经取代的铵离子(例如N(R1)(R2)(R3)(R4)+型离子,其中R1、R2、R3及R4一般将独立地表示氢、任选地为经取代的C1-6烷基或任选地经取代的C2-6烯基)的盐。相关C1-6烷基基团的实例包括甲基、乙基、1-丙基和2-丙基基团。可能相关的C2-6烯基的实例包括乙烯基、1-丙烯基和2-丙烯基。可药用盐的另一些实例描述于“Remington’s Pharmaceutical Sciences”,第17版,Alfonso R.Gennaro(编),Mark Publishing Company,Easton,PA,USA,1985(及其最近版本)、“Encyclopaedia of Pharmaceutical Technology”,第3版,James Swarbrick(编),Informa Healthcare USA(Inc.),NY,USA,2007和J.Pharm.Sci.66:2(1977)中。
本发明上下文中的术语“溶剂合物”指在溶质(在此情形下为根据本发明之肽缀合物或其可药用盐)与溶剂之间形成的指定化学计量的复合物。在此关系中的溶剂可以是例如水、乙醇,或另一可药用的一般小分子的有机物质,例如但不限于乙酸或乳酸。当所关注的溶剂为水时,这种溶剂合物通常称为水合物。
本发明的一些实施方案涉及根据本发明的肽缀合物或其可药用盐用作药物或用于制造或制备药物,或者涉及肽缀合物或其可药用盐在治疗或预防多种疾病或病状的方法中的用途,例如:
1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、葡萄糖耐量糖耐量减低(impaired glucose tolerance,IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常(atherogenicdyslipidemia)、动脉硬化(例如动脉粥样硬化)、大血管疾病、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(inflammatory bowel disease,IBD)、肠易激综合征(irritable bowel syndrome,IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭。
在此关系中可能相关的另一些疾病或病症包括肥胖、病态肥胖、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。
在一些实施方案中,本发明的药物为用于治疗有此需要之对象的药物。
在另一些实施方案中,本发明的药物为用于在有此需要的对象中诱导胰岛新生(例如用于促进胰岛中新β细胞的形成)的药物。
在另一些实施方案中,本发明的药物为用于在有此需要的对象中诱导胰岛中β细胞存活(例如用于预防胰岛中β细胞的损失)的药物。
在另一些实施方案中,本发明的药物为用于在有此需要的对象中诱导胰岛中β细胞增殖(例如促进胰岛中现有β细胞的增殖)的药物。
在另一些实施方案中,本发明的药物为用于在有此需要的对象中诱导以上提及过程(即胰岛新生、胰岛中的β细胞存活和/或胰岛中的β细胞增殖)之任意组合的药物。
根据实施方案权利要求39之肽缀合物或者其可药用盐或溶剂合物的用途,其中该药物用于在有此需要的对象中提高胰岛β细胞的存活率。
在另一些实施方案中,本发明的药物为用于在有此需要的对象中预防胰岛中β细胞凋亡和/或坏死(例如用于预防胰岛中β细胞的损失)的药物。
在另一些实施方案中,本发明的药物为用于在有此需要的对象中降低血液中血红蛋白b1Ac(糖基化血红蛋白;HbA1c)水平的药物。
本发明的另一个方面涉及本发明的肽缀合物在制造或制备用于在有此需要的对象中治疗一种或更多种本文所公开的病状的药物中的用途。
本发明的肽缀合物还可用于:
制造用于在有此需要的对象中诱导胰岛新生的药物;
制造用于在有此需要的对象中预防胰岛中β细胞凋亡的药物;
制造用于在有此需要的对象中诱导胰岛中β细胞存活的药物;
制造用于在有此需要的对象中诱导胰β细胞增殖的药物;
制造用于在有此需要的对象的血液中降低血红蛋白b1Ac(糖基化血红蛋白;HbA1c)水平的药物;
和/或其任意组合。
本发明另外相关的方面为治疗本文所公开之病状、疾病或病症的相应方法。因此,本发明的一个这种另外的方面涉及在有此需要的对象中治疗一种或更多种本文所公开之疾病、病症或病状的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者其可药用盐或溶剂合物。
本发明的另一些实施方案涉及用于在有此需要的对象中诱导胰岛新生的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者可药用盐或溶剂合物。
本发明的另一些实施方案涉及在有此需要的对象中促进胰岛中β细胞存活的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者其可药用盐或溶剂合物。
本发明的另一些实施方案涉及用于在有此需要的对象中降低或预防胰岛中β细胞凋亡和/或坏死的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者其可药用盐或溶剂合物。
本发明的另一些实施方案涉及用于在有此需要的对象中诱导胰岛中β细胞增殖的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者其可药用盐或溶剂合物。
本发明的另一些实施方案涉及用于在有此需要的对象中诱导上文提及过程(即胰岛新生、胰岛中β细胞存活和/或胰岛中β细胞增殖)之任何组合的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者其可药用盐或溶剂合物。
本发明的另一些实施方案涉及用于在有此需要的对象的血液中降低血红蛋白b1Ac(糖基化血红蛋白;HbA1c)水平的方法,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或其可药用盐或溶剂合物。
本发明的另一些实施方案涉及以下:
在有此需要的对象中治疗与血糖水平升高相关之疾病状态的方法;
在有此需要的对象中降低血糖水平的方法;
在有此需要的对象中刺激胰岛素释放的方法;
在有此需要的对象中调节胃排空的方法;以及
在有此需要的对象中降低血浆脂质水平的方法;
在有此需要的对象中减低血压的方法;
在有此需要的对象中减轻体重的方法。
在本发明的每一后续方法中,该方法包括向对象施用治疗有效量的根据本发明的肽缀合物或者其可药用盐或溶剂合物。
如根据本发明的上述治疗方法或其他治疗性干预之情形下所采用的术语“治疗有效量”指例如由确定临床终点或其他生物标记(确定的或实验的)所测量的足以治愈、改善、缓解或部分阻止所关注治疗或其他治疗性干预目标的特定疾病、病症或病状之临床表现的量。治疗相关量可基于待治疗或预防的适应症以及治疗相关量所施用的对象由本领域技术人员凭经验确定。例如,本领域技术人员可测量本文所述生物活性的一种或更多种临床相关指标,例如血糖水平、胰岛素释放和血浆脂质水平。本领域技术人员可通过体外或体内测量确定临床相关量。另一些示例性量度包括体重增长、体重减轻和血压变化。
足以达成任何或所有这些效果的量被定义为治疗有效量。可调整施用的量和施用方法来达成最佳效力。对于指定目的有效的量将特别地取决于作为特定治疗或其他治疗性干预目标之疾病、病症或病状的严重度、所关注对象的体重和一般状况、饮食、可能并用的药物以及医药领域技术人员公知的其他因素。最适合向人施用根据本发明的肽缀合物或者其可药用盐或溶剂合物的适当剂量大小以及给药方案的确定可由本发明获得的结果来指导,且可以适当设计的临床试验来证实。有效剂量和治疗方案可由常规手段确定,在实验室动物中由低剂量开始且随后提高剂量,同时监测效果,且还系统地变化剂量方案。临床医师在确定用于指定对象的最佳剂量时可考虑许多因素。这些考虑为本领域技术人员所公知。
如本发明上下文所采用的术语“治疗(treatment)”及其语法变化(例如“治疗(treated)”、“治疗(treating)”、“治疗(treat)”)指获得有益或期望的临床结果的途径。就本发明的目的而言,有益或期望的临床结果包括但不限于症状缓解、疾病程度降低、疾病状态稳定(即不恶化)、疾病进展延迟或减缓、疾病状态改善或缓和以及缓解(无论部分或总体),而无论可检测或不可检测。“治疗”也可意指若未接受治疗,则相对于预期存活时间延长存活。需要治疗的对象(例如人)因此可以是已罹患所关注疾病或病症的对象。术语“治疗”包括相对于不存在治疗来说抑制或降低病理状态或症状(例如体重增长或高血糖)之严重度的提高,且不一定意在表示相关疾病、病症或病状的完全停止。
如本发明上下文所采用的术语“预防(preventing)”及其语法变化(例如“预防(prevented)”、“预防(preventing)”、“预防(prevent)”指预防病状、疾病或病症形成或改变其病理学的途径。因此,“预防(prevention)”可指防止性(prophylactic)或预防性措施。在本发明中,有益或期望的临床结果包括但不限于预防或减缓疾病的症状、进展或发生,而无论可检测或不可检测。需要预防的对象(例如人)因此可以是尚未罹患所关注疾病或病症的对象。术语“预防”因此包括相对于不存在治疗来说减缓疾病的发作,且不一定意在表示相关疾病、病症或病状的永久预防。
如本发明上下文所采用的术语“激动剂”指使所关注受体类型活化的物质(配体)。
如本发明上下文所采用的术语“GLP-1受体激动剂”(有时在别处称作“GLP-1激动剂”)指使GLP-1受体(例如人GLP-1受体)活化的物质(配体)。使人类GLP-1受体活化的物质包括天然GLP-1肽激素GLP-1(7-37)、GLP-1(7-36)酰胺、泌酸调节肽、毒蜥外泌肽-3、毒蜥外泌肽-4、胰高血糖素、胃抑制多肽(gastric inhibitory polypeptide,GIP)及其功能性肽类似物和衍生物。
如本发明上下文所采用的术语“拮抗剂”指阻断、中和或抵消发挥激动剂功能的另一物质(配体)对所关注受体类型之作用的物质(配体)。
在本发明的一些实施方案中,联系上述本发明的多个方面而提及的需要特定治疗或其他治疗性干预的对象为哺乳动物。在另一些实施方案中,该哺乳动物为人。
本发明的另外一些实施方案涉及包含根据本发明之肽缀合物或者其可药用盐或溶剂合物连同可药用载体、赋形剂或载剂的药物组合物。
肽缀合物的合成
本发明的肽缀合物可通过标准合成方法,通过使用重组表达系统或通过任何其他合适的方法来制造。因此,缀合物可由多种方式来合成,包括例如包括以下的方法:
(a)通过标准固相或液相方法逐步或通过片段组装合成肽缀合物,且分离并纯化最终肽缀合物产物;
(b)在宿主细胞中表达编码肽缀合物的核酸构建体并自宿主细胞培养物回收表达产物;或
(c)影响编码肽缀合物之核酸构建体的无细胞体外表达,并回收表达产物;或通过方法(a)、(b)或(c)的任意组合来获得肽缀合物的片段,随后连接这些片段以获得肽缀合物,并回收肽缀合物。
可优选地通过固相或液相肽合成手段来合成本发明的缀合物。在本文中,可参考WO98/11125或特别地参考Fields,G.B.等,“Principles andPractice of Solid-Phase Peptide Synthesis”;Synthetic Peptides,Gregory A.Grant(编),Oxford University Press(第2版,2002)以及本文中的合成实施例。
本发明化合物中的一个或更多个氨基酸侧链可进一步与亲脂性取代基缀合。亲脂性取代基可与氨基酸侧链中的原子共价结合,或者作为替代地可通过间隔区与氨基酸侧链缀合。氨基酸可以是肽Z的部分或肽L的一部分。
不希望受理论束缚,认为亲脂性取代基结合血流中的白蛋白,因此使本发明化合物免于酶促降解,这可延长化合物的半衰期。间隔区(存在时)可在化合物与亲脂性取代基之间提供间隔。
亲脂性取代基可由酯、磺酰基酯、硫酯、酰胺或磺酰胺与氨基酸侧链或间隔区相连接。因此,应了解,在一些实施方案中,亲脂性取代基包括酰基、磺酰基、N原子、O原子或S原子,其形成酯、磺酰基酯、硫酯、酰胺或磺酰胺的一部分。
优选地,亲脂性取代基中的酰基形成具有氨基酸侧链或间隔区的酰胺或酯的一部分。
亲脂性取代基可包括具有4至30个C原子、例如至少8或12个C原子且优选的24个或以下C原子或者20个或以下C原子的烃链。该烃链可以是直链或支链的且可以是饱和或不饱和的。应了解,烃链优选地经形成与氨基酸侧链或间隔区连接之一部分的部分(例如酰基、磺酰基、N原子、O原子或S原子)取代。最优选地,烃链经酰基取代,并因此烃链可以是烷酰基的部分,例如棕榈酰基、己酰基、月桂酰基、肉豆蔻酰基或硬脂酰基。
因此,亲脂性取代基可具有以下所示的式:
A可以是例如酰基、磺酰基、NH、N-烷基、O原子或S原子,优选为酰基。n为3至29的整数。在一些实施方案中,n至少为7或至少为11。在一些实施方案中,n为23或以下。在一些实施方案中,n为19或以下。
烃链可经进一步取代。例如,其还可经至多三个选自NH2、OH和COOH的取代基取代。若烃链经进一步取代,则其优选地仅经一个取代基进一步取代。作为替代或补充,烃链可包括环烷或杂环烷,例如如以下所示:
在一些实施方案中,环烷或杂环烷为六元环。在某些优选的实施方案中,其为哌啶。
或者,亲脂性取代基可基于环戊菲骨架,其可以是部分或完全不饱和或饱和。骨架中的碳原子各自可经Me或OH取代。例如,亲脂性取代基可以是胆酰基(cholyl)、脱氧胆酰基或石胆酰基。
如上所表明,亲脂性取代基可通过间隔区与氨基酸侧链缀合。存在时,间隔区连接至亲脂性取代基并与氨基酸侧链相连接。间隔区可通过酯、磺酰基酯、硫酯、酰胺或磺酰胺独立地与亲脂性取代基相连接并与氨基酸侧链相连接。因此,其可包括两个独立地选自酰基、磺酰基、N原子、O原子或S原子的部分。间隔区可具有下式:
其中B和D各自独立地选自酰基、磺酰基、NH、N-烷基、O原子或S原子,优选地选自酰基和NH。优选地,n为1至10、例如1至5的整数。间隔区可任选地经一个或更多个选自C1-6烷基、C1-6烷基胺、C1-6烷基羟基和C1-6烷基羧基的取代基进一步取代。
或者,间隔区可具有两个或更多个上式的重复单元。对于每一重复单元而言,B、D及n各自独立地选择。相邻重复单元可由其各自的B及D部分彼此共价连接。例如,相邻重复单元的B和D部分可一起形成酯、磺酰基酯、硫酯、酰胺或磺酰胺。每一间隔区末端处的自由B和D单元与如上所述的氨基酸侧链和亲脂性取代基相连接。
间隔区优选地具有5个或以下、4个或以下或者3个或以下的重复单元。间隔区最优选地具有两个重复单元或为单个单元。
间隔区(或若其具有重复单元,则为一个或更多个间隔区重复单元)可以是例如天然或非天然氨基酸。应了解,对于具有官能化侧链的氨基酸而言,B和/或D可以是氨基酸侧链内的部分。间隔区可以是任何天然产生或非天然的氨基酸。例如,间隔区(或若其具有重复单元,则为一个或更多个间隔区重复单元)可以是Gly、Pro、Ala、Val、Leu、Ile、Met、Cys、Phe、Tyr、Trp、His、Lys、Arg、Gln、Asn、α-Glu、γ-Glu、Asp、Ser Thr、Gaba、Aib、bAla、5-氨基戊酰基、6-氨基己酰基、7-氨基庚酰基、8-氨基辛酰基、9-氨基壬酰基或10-氨基癸酰基。
例如,间隔区可以是选自γ-Glu、Gaba、b-Ala和α-Gly的单个氨基酸。
亲脂性取代基可本发明化合物中的任何氨基酸侧链缀合。优选地,氨基酸侧链包括羧基、羟基、巯基、酰胺或胺基,以供与间隔区或亲脂性取代基形成酯、磺酰基酯、硫酯、酰胺或磺酰胺。例如,亲脂性取代基可与Asn、Asp、Glu、Gln、His、Iys、Arg、Ser、Thr、Tyr、Trp、Cys或Dbu、Dpr或Orn缀合。优选地,亲脂性取代基与Lys或Cys缀合。然而,如本文所提供的式中以Lys显示的任何氨基酸在添加亲脂性取代基时可由Dbu、Dpr或Orn替换。
亲脂性取代基和间隔区的一个实例在下式中显示:
此处,来自本发明化合物(例如来自X)的Lys经由酰胺部分与γ-Glu(间隔区)共价连接。棕榈酰基经由酰胺部分与γ-Glu间隔区共价连接。
作为替代或补充,本发明化合物中的一个或更多个氨基酸侧链可进一步缀合至生物素基取代基。生物素基取代基可与氨基酸侧链中的原子共价结合,或作为替代地可通过间隔区与氨基酸侧链缀合。氨基酸可以是肽Z的部分或肽L的一部分。
不希望受理论束缚,认为生物素基取代基结合血流中的白蛋白,因此使本发明化合物免于酶促降解,这可延长化合物的半衰期。间隔区(存在时)用于在化合物与生物素基取代基之间提供间隔。
生物素基取代基可经由马来酰亚胺酯、磺酰基酯、硫酯、酰胺或磺酰胺与氨基酸侧链相连接或与间隔区相连接。因此,应了解,生物素基取代基优选地包括马来酰亚胺基、酰基、磺酰基、N原子、O原子或S原子,其形成酯、磺酰基酯、硫酯、酰胺或磺酰胺的一部分。
在一些优选的实施方案中,生物素部分首先与间隔区偶联,之后间隔区与肽偶联。可商业上得到多种具有允许与赖氨酸或半胱氨酸的侧链偶联之间隔区官能团的生物素-间隔区缀合物。在一些更优选的实施方案中,生物素-间隔区缀合物含有可选择性地与半胱氨酸侧链上的巯基偶联的马来酰亚胺官能团。
根据本发明可用的生物素基取代基的实例包括:
生物素被称作维生素H或辅酶R且为水溶性B-复合维生素(维生素B7)。已显示其提高某些药物的经口摄取。
作为替代或补充,本发明化合物中的一个或更多个氨基酸侧链可与聚合物部分缀合,例如以提高溶解性和/或体内(例如在血浆中)的半衰期和/或生物利用度。还已知该修饰降低治疗性蛋白质和肽的清除率(例如肾清除率)。
聚合部分优选地为水溶的(两亲的或亲水的)、无毒的且呈药学上惰性的。合适的聚合部分包括聚乙二醇(PEG)、PEG的均聚物或共聚物、PEG的单甲基取代的聚合物(mPEG)或聚氧乙烯甘油(POG)。参见例如Int.J.Hematology68:1(1998);Bioconjugate Chem.6:150(1995);以及Crit.Rev.Therap.Drug CarrierSys.9:249(1992)。
另一些合适的聚合部分包括聚氨基酸,例如聚赖氨酸、聚天冬氨酸和聚谷氨酸(参见例如Gombotz等,(1995),Bioconjugate Chem.,第6卷:332-351;Hudecz等,(1992),Bioconjugate Chem.,第3卷,49-57;Tsukada等,(1984),J.Natl.Cancer Inst.,第73卷:721-729;以及Pratesi等,(1985),Br.J.Cancer,第52卷:841-848)。
聚合部分可以是直链或分支的。其可具有500至40,000Da,例如500至10,000Da、1000至5000Da、10,000至20,000Da或20,000至40,000Da的分子量。
本发明的化合物可包含两个或更多个这些部分,在此情形下所有这些部分的总分子量通常将在上文提供的范围内。
聚合部分可与氨基酸侧链的氨基、羧基或巯基基团偶联(通过共价连接)。优选的实例为Cys残基的巯基和Lys残基的ε氨基,且还可使用Asp和Glu残基的羧基。
技术人员将充分知晓可用来进行偶联反应的合适技术。例如,带有甲氧基基团的PEG部分可使用购自Nektar Therapeutics AL的试剂,通过马来酰亚胺基键合与Cys巯基基团偶联。合适化学的详情也参见WO2008/101017以及上文引用的参考文献。
在本发明的一些实施方案中,经马来酰亚胺官能化的PEG与半胱氨酸的侧链巯基缀合。
效力
本发明的肽缀合物具有毒蜥外泌肽-4的一种或更多种生物活性以及胃泌素的一种或更多种生物活性。
在不存在胃泌素样组分Y(Ya,Yb)及任何接头组分L(La,Lb)下,肽Z(Za,Zb)具有毒蜥外泌肽-4的一种或更多种生物活性。也就是说,化合物R1-Z-R2将具有毒蜥外泌肽-4的所述一种或更多种生物活性。
在不存在毒蜥外泌肽-4样组分Z(Za,Zb)及任何接头组分L(La,Lb)下,肽Y(Ya,Yb)具有胃泌素的一种或更多种生物活性。也就是说,化合物R1-Y-R2将具有胃泌素的所述一种或更多种生物活性。
毒蜥外泌肽-4的生物活性可以是对于GLP-1受体的激动剂活性。胃泌素的生物活性可以是对于CCK-B受体的激动剂活性。
优选地,激动剂活性是对人GLP-1受体和/或人CCK-B受体的激动剂活性。“激动剂活性”可包括对于结合至相关受体而诱导细胞内环AMP(cAMP)合成或pERK磷酸化的能力。
因此,相关化合物与GLP-1或CCK-B受体的结合可用作激动剂活性的指示,但一般而言优选地使用测量由化合物与相关受体结合引起之细胞内信号传导的生物测定。例如,通过合适激动剂活化GLP-1受体将刺激细胞cAMP形成。类似地,通过合适激动剂活化CCK-B受体将刺激细胞pERK磷酸化。因此,在表达这两种受体之一的合适细胞中cAMP的产生或ERK的磷酸化(pERK)可用来监测相关受体活性。使用一对合适细胞类型,各自表达一种受体而不表达另一种,因此可用来确定对于两种受体类型的激动剂活性。
本领域技术人员将知晓合适的测定形式,且下文提供了实例。测定可采用人GLP-1受体(NP_002053.3GI:166795283)和/或人类CCK-B受体(NM_176875.3GI:356995851)。当提及前体蛋白的序列时,当然应了解测定可利用缺少信号序列的成熟蛋白质。
在一个优选的实施方案中,本发明的多肽对于GLP1-R可具有低于0.1nM的EC50值。
在一些实施方案中,本发明的多肽对于CCKB-R可具有低于100nM的EC50值。
在一个优选的实施方案中,本发明的多肽对于CCKB-R可具有低于50nM的EC50值。
EC50值应如实施例4中所描述的进行测量。
治疗用途
本发明之肽缀合物的用途还涵盖其可药用盐或溶剂合物的用途。
本发明之肽缀合物可为代谢疾病或病症(包括糖尿病(特别是1型和/或2型糖尿病)及肥胖)提供具吸引力的治疗选择。
糖尿病包括一组代谢疾病,其特征为由胰岛素分泌、胰岛素作用或二者的缺陷所致的高血糖。糖尿病的急性体征包括尿液产生过多、随之发生的代偿性口渴和流体摄入提高、视力模糊、不明原因体重减轻、嗜眠及能量代谢变化。糖尿病的慢性高血糖与大血管和微血管并发症有关,这些并发症可导致多种器官(特别是眼睛(特别以糖尿病性视网膜病形式)、肾(以糖尿病性肾病形式)、神经(以糖尿病性神经病形式)、心脏和血管)的长期损伤、功能障碍以及(在某些情况下)最终衰竭。糖尿病可基于发病特征细分为三类,即1型糖尿病、2型糖尿病和妊娠糖尿病。
1型糖尿病占所有糖尿病病例的5-10%且由分泌胰岛素之胰β细胞的自身免疫破坏引起。
2型糖尿病占糖尿病病例的90-95%且为代谢病症复杂集合的结果。2型糖尿病是内源性胰岛素产生和/或全身胰岛素敏感性变得不足以将血浆葡萄糖水平维持在诊断阈值以下的结果。
妊娠糖尿病指在怀孕期间鉴定的任何程度的葡萄糖不耐受。
还识别称作前驱糖尿病的病状。其包括例如空腹葡萄糖水平升高和葡萄糖耐量糖耐量减低,且通常指在血糖水平升高但低于关于临床诊断糖尿病所确立的水平时发生的那些状态。
大部分患有2型糖尿病及前驱糖尿病的对象由于另外代谢风险因素的高普遍性而存在发病率及死亡率提高的风险,这些代谢风险因素包括腹部肥胖(腹部内部器官周围过多的脂肪组织)、致动脉粥样硬化的血脂异常(血脂病症,包括高甘油三酯水平、低HDL胆固醇水平和/或高LDL胆固醇水平,其促进动脉壁中的斑积聚(plaque build-up))、血压升高(高血压)、血栓前状态(prothrombotic state)(例如血液中的高血纤维蛋白原或纤维蛋白溶酶原活化因子抑制剂-1水平)和促炎性状态(例如血液中C-反应性蛋白水平升高)。
相反地,肥胖使得发生例如前驱糖尿病、2型糖尿病、某些类型的癌症、阻塞性睡眠呼吸暂停和胆囊疾病的风险提高。
血脂异常与心血管疾病的风险提高有关。由于血浆高密度脂蛋白(High Density Lipoprotein,HDL)浓度与动脉粥样硬化疾病风险之间存在负相关性,因此HDL具有临床重要性。动脉粥样硬化斑中储存的大部分胆固醇源自低密度脂蛋白(Low Density Lipoprotein,LDL),因此LDL的浓度升高与动脉粥样硬化密切相关。HDL/LDL比值是特别用于评估动脉粥样硬化和冠状动脉粥样硬化之临床风险的参数。
不受任何特定理论限制,本发明的肽缀合物看来可出乎意料地以使得所观察的活性可显著大于在采用个别肽组分之相应添加(非缀合)组合时所观察的活性的方式组合GLP-1受体激动剂的生理学作用与胃泌素肽的生理学作用(见上)。因此,认为本发明的肽缀合物可特别有益于治疗前驱糖尿病、糖尿病(特别是1型和/或2型糖尿病)及如上所讨论的那些糖尿病相关病状、疾病或病症,包括治疗以促进胰岛β细胞形成(胰岛新生)并因此促进胰岛素产生,其将对血糖浓度的调节有益。因此,本发明的肽缀合物可特别地在限制或阻止1型和/或2型糖尿病的疾病进展中有价值。
本发明的肽还可用于促进胰岛中β细胞的存活并且还抑制其凋亡。GLP-1和胃泌素的作用包括对β细胞增殖和成熟的作用,并且预防β细胞凋亡和/或坏死以及增强新生,因此本发明之肽的作用可包括这些作用及其对于改善胰岛素和葡萄糖调节的作用。
本发明的肽缀合物可因此用作用于治疗本文所述任何疾病、病症或病状的药剂。示例性疾病、病症或病状包括胰岛素抗性、葡萄糖不耐受、前驱糖尿病、与血糖水平升高相关的疾病状态(例如空腹血糖水平升高)、1型和/或2型糖尿病、高血糖、胃病、代谢综合征、高血压和/或血脂异常(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、微血管疾病、大血管疾病、外周动脉疾病、卒中、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭。
治疗的示例性作用包括预防体重增长、促进体重减轻、降低体重过重和/或治疗肥胖(例如通过控制食欲、进食、食物摄取、热量摄取和/或能量消耗),包括病态肥胖以及相关疾病、病症和健康状况,包括但不限于肥胖相关炎症、肥胖相关胆囊疾病以及肥胖诱发的睡眠呼吸暂停。本发明的肽缀合物对这些病状的作用可经由对体重的作用而整体或部分介导,或可不依赖于这些。
药物组合物
下文中,应了解,提及在药物组合物中包含一种或更多种本发明的肽缀合物还涵盖包含本发明之肽缀合物的可药用盐或溶剂合物。
本发明的肽缀合物可配制成适合经储存或不经储存而施用的药物组合物,且其一般包含治疗有效量的至少一种本发明的肽缀合物以及可药用载体、赋形剂或载剂。
术语“可药用载体”包括任何标准药用载体。用于治疗用途之可药用载体在药物领域中是公知的,且描述于例如“Remington’s PharmaceuticalSciences”,第17版,Alfonso R.Gennaro(编),Mark Publishing Company,Easton,PA,USA,1985中。例如,可使用无菌盐水和微酸性或生理pH的磷酸盐缓冲盐水。合适pH的缓冲剂可以是例如磷酸盐、柠檬酸盐、乙酸盐、三(羟甲基)氨基甲烷(TRIS)、N-三(羟甲基)甲基-3-氨基丙磺酸(TAPS)、碳酸氢铵、二乙醇胺、组氨酸、精氨酸、赖氨酸或乙酸盐(例如乙酸钠)或其混合物。该术语还涵盖美国药典中所列举的任何用于动物(包括人)的载体试剂。
本发明的药物组合物可以是单位剂型。在这样的形式中,组合物被分成含有合适量的活性组分的单位剂量。单位剂型可呈现为包装的制剂,该包装含有离散量的制剂,例如在小瓶或安瓿中包装的片剂、胶囊剂或散剂。单位剂型本身还可以是例如胶囊剂、扁囊剂(cachet)或片剂,或者其可以是合适数量的任意这些包装的形式。单位剂型也可以单剂量注射形式提供,例如以含有液相(一般水相)组合物的笔(pen)装置形式。组合物可配制成用于任何适合的施用途径和方式。可药用载体或稀释剂包括在合适的例如经口、经玻璃体内、经直肠、经阴道、经鼻、表面、经肠或胃肠外(包括皮下(SC)、肌内(IM)、静脉内(IV)、真皮内和透皮)施用或通过吸入施用的制剂中使用的那些。制剂可常规地呈现为单位剂型且可通过药物制剂领域中任何公知的方法来制备。
皮下或透皮施用方式可特别适合于本发明的肽缀合物。
本发明的另一个方面涉及用来递送本发明之药物制剂的装置、剂型和包装。因此,如本领域中所公知,在本文所述之稳定或保藏制剂或溶液中的至少一种肽缀合物或特定部分或变体可根据本发明经由多种递送方法向患者施用,包括SC或IM注射;透皮、经肺、经粘膜、植入、渗透泵、筒(cartridge)、微泵,或本领域技术人员了解的其他方式。
本发明的另一个方面涉及经口制剂及施用。用于经口施用的制剂可依赖助剂的共施用(例如间苯二酚及非离子表面活性剂,例如聚氧乙烯油基醚和正十六烷基聚乙烯醚)以人工提高肠壁的渗透性,以及酶促抑制剂(例如胰蛋白酶抑制剂、氟磷酸二异丙酯(DFF)和抑肽酶)的共施用以抑制酶促降解。用于经口施用之固体剂型的活性成分化合物可与至少一种添加剂混合,包括蔗糖、乳糖、纤维素、甘露糖醇、海藻糖、棉子糖、麦芽糖醇、葡聚糖、淀粉、琼脂、精氨酸盐(arginate)、甲壳质、壳聚糖、果胶、西黄蓍胶、阿拉伯树胶、明胶、胶原、酪蛋白、白蛋白、合成或半合成聚合物和甘油酯。这些剂型还可含有另一些类型的添加剂,例如非活性稀释剂、润滑剂(例如硬脂酸镁、对羟基苯甲酸酯)、防腐剂(例如山梨酸、抗坏血酸、α-生育酚)、抗氧化剂(例如半胱氨酸)、崩解剂、黏合剂、增稠剂、缓冲剂、pH调节剂、甜味剂、矫味剂、香味剂等。
剂量
本发明的上下文中所用之本发明肽缀合物的典型剂量可在每天每公斤体重约0.0001至约100mg的范围内,例如每天每公斤体重约0.0005至约50mg,例如每天每公斤体重约0.001至约10mg,例如每天每公斤体重约0.005至约5mg,例如每天每公斤体重约0.01至约1mg,例如每天每公斤体重约0.015至约0.1mg,以一个或更多个剂量,例如一个至三个剂量施用。如上文某种程度所表明,所用精确的剂量将特别地取决于:欲治疗疾病或病症的性质和严重度;欲治疗对象的性别、年龄、体重和一般状况;正接受或将接受治疗之其他可能的并发疾病或病症;以及将为本领域技术医师所知的其他因素。
本发明的肽缀合物可视熟练医师为特定对象选择的所需剂量和药物组合物而连续施用(例如通过静脉内施用或其他连续药物施用方法)或以一定间隔(一般以规律的时间间隔)向对象施用。
规律施用给药间隔包括例如每天一次、每天两次、每两天一次、每三天一次、每四天一次、每五天一次或每六天一次、每周一或两次、每月一或两次或者规律的和更不频繁的给药间隔,取决于特定剂量制剂、生物利用度以及肽缀合物的药物代谢动力学图谱(pharmacokinetic profile)。
本发明的该规律肽缀合物施用方案在某些情况下(例如在慢性长期施用期间)宜中断一定时间间隔以使得经药物治疗的对象降低药物水平或停止服药,通常称作采用“药物假期(drug holiday)”。药物假期用于例如维持或重获药物敏感性(特别是在长期慢性治疗期间)或降低药物长期慢性治疗对对象之不必要的副作用。
药物假期的时间取决于规律给药方案的时间及采用药物假期之目的(例如为了重获药物敏感性和/或降低连续长期施用的不必要副作用)。在一些实施方案中,药物假期可以是药物的降低(例如在一定时间间隔低于治疗有效量)。在另一些实施方案中,在再次开始施用之前,在相同或不同给药方案(例如以较低或较高剂量和/或施用频率)下停止使用药物一定时间间隔。
因此,肽缀合物可经由包括两个或更多个通过分别的药物假期阶段分开之施用阶段的施用方案。
在每个施用阶段,根据预先确定的施用方式向受体对象以治疗有效量施用肽缀合物。该施用方式可包括在整个施用阶段的持续时间中向受体对象连续施用药物。或者,施用方式可包括向受体对象施用多个剂量的肽缀合物,其中所述剂量通过给药间隔隔开。
给药方式每个施用阶段可包含至少两个剂量,每个施用阶段至少5个剂量,每个施用阶段至少10个剂量,每个施用阶段至少20个剂量,每个施用阶段至少30个剂量,或更多。
所述给药间隔可以是规律给药间隔,其可如上文所列出,包括每天一次、每天两次、每两天一次、每三天一次、每四天一次、每五天一次或每六天一次、每周一或两次、每月一或两次或者规律的和更不频繁的给药间隔,取决于特定剂量制剂、生物利用度以及肽缀合物的药物代谢动力学图谱。
施用阶段可具有至少两天、至少一周、至少两周、至少四周、至少一个月、至少两个月、至少三个月、至少六个月或更长的持续时间。
当施用方式包括多个剂量,接下来之药物假期阶段的持续时间长于在该施用方式中使用的给药间隔。当给药间隔不规律,药物假期阶段的持续时间可大于该施用阶段整个进程剂量间的平均间隔。或者,药物假期的持续时间可长于在该施用阶段期间连续剂量间的最长间隔。
药物假期阶段的持续时间可以是相关给药间隔(或其平均值)的至少2倍、至少3倍、至少4倍、至少5倍、至少10倍或者相关给药间隔或其平均值的至少20倍。
在这些限制下,药物假期阶段可具有至少两天、至少一周、至少两周、至少四周、至少一个月、至少两个月、至少三个月、至少六个月或更长的持续时间,取决于之前施用阶段期间的施用方式。
施用方案包含至少两个施用阶段。通过分别的药物假期阶段将连续的施用阶段分开。因此,施用方案可包括至少3个、至少4个、至少5个、至少10个、至少15个、至少20个、至少25个或至少30个施用阶段,或者更多,每个都通过分别的药物假期阶段分开。
连续施用阶段可利用相同的施用方式,虽然这不总是期望或必须的。然而,如果其他药物或活性剂与本发明的肽缀合物组合施用,则一般相同组合的药物或活性剂以连续施用阶段给予。在某些实施方案中,受体对象是人。
组合疗法
如上所述,应了解下文中提及本发明的肽缀合物还延伸至其可药用盐或溶剂合物以及包含一种以上不同本发明肽缀合物的组合物。
本发明的肽缀合物可作为组合疗法之部分同另一种活性剂一起施用用于治疗所关注的疾病或病症,例如糖尿病、肥胖、代谢综合征、血脂异常或高血压,且在这些情形下,两种活性剂可一起或单独给予,例如作为同一药物组合物或制剂中的组分或作为单独制剂。
因此,本发明的肽缀合物可与已知类型的抗糖尿病剂组合使用,包括但不限于二甲双胍、磺酰脲类、格列奈类(glinide)、DPP-IV抑制剂、格列酮类(glitazone)或者胰岛素或胰岛素类似物。在一个优选的实施方案中,本发明的肽缀合物与胰岛素或其类似物、DPP-IV抑制剂、磺酰脲类或二甲双胍(特别是磺酰脲类或二甲双胍)组合施用,用于实现充分的血糖控制。在一个更优选的实施方案中,肽缀合物与胰岛素或胰岛素类似物组合施用,用于实现充分的血糖控制。适当胰岛素类似物的实例包括但不限于LantusTM、NovorapidTM、HumalogTM、NovomixTM、ActraphaneTMHM、LevemirTM DegludecTM和ApidraTM。就此而言,其他相关抗糖尿病剂包括GLP-1受体激动剂,例如艾塞那肽(exenatide)(ByettaTM;毒蜥外泌肽-4)及Byetta LARTM、利西拉肽(lixisenatide)(LyxumiaTM)和利拉鲁肽(liraglutide)(VictozaTM)。
本发明的肽缀合物还可与已知类型的抗肥胖剂组合使用,包括但不限于肽YY或其类似物、神经肽Y(NPY)或其类似物、大麻素受体(cannabinoid receptor)1拮抗剂、脂肪酶抑制剂、人前胰岛肽(Humanproislet peptide,HIP)、黑皮质素受体4激动剂、利拉鲁肽、OrlistatTM和SibutramineTM或黑色素聚集激素(melanin concentrating hormone)受体1拮抗剂、CCK、胰淀素或瘦素及其类似物。
本发明的肽缀合物还可与已知类型的抗高血压剂组合使用,其包括但不限于血管紧张素转化酶抑制剂、血管紧张素II受体阻断剂、利尿剂、β-阻断剂或钙通道阻断剂。
本发明的肽缀合物还可与已知类型的抗血脂异常剂组合使用,包括但不限于他汀类(statin)、贝特类(fibrate)、烟酸类和/或胆固醇吸收抑制剂。
本发明的肽缀合物还可与已知类型的质子泵抑制剂(即具有作为H+K+-ATP酶抑制剂之药理活性的药剂)组合使用,包括但不限于苯并咪唑衍生物类型或咪唑并吡啶衍生物类型的剂,例如OmeprazoleTM、LansoprazoleTM、DexlansoprazoleTM、EsomeprazoleTM、PantoprazoleTM、RabeprazoleTM、ZolpidemTM、AlpidemTM、SaripidemTM或NecopidemTM。
此外,本发明的肽缀合物可与已知类型的抗炎剂组合使用,包括但不限于:
类固醇及皮质类固醇,例如倍氯松(beclomethasone)、甲基泼尼松龙(methylprednisolone)、倍他米松(betamethasone)、泼尼松(prednisone)、地塞米松(dexamethasone)和氢化可的松(hydrocortisone);
非类固醇抗炎剂(non-steroidal antiinflammatory agent,NSAID),例如丙酸衍生物(例如阿明洛芬(alminoprofen)、苯洛芬(benoxaprofen)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufcn)、非诺洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、丙嗪(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)和硫洛芬(tioxaprofen));乙酸衍生物(例如吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、环氯茚酸(clidanac)、双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、呋罗芬酸(furofenac)、异丁布芬酸(ibufenac)、伊索克酸(isoxepac)、欧比那酸(oxpinac)、舒林酸(sulindac)、噻平酸(tiopinac)、托美汀(tolmetin)、齐多美辛(zidometacin)和佐美酸(zomepirac));芬那酸(fenamic acid)衍生物(例如氟芬那酸(flufenamic acid)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、尼氟酸(niflumic acid)和托芬那酸(tolfenamic acid));联苯基羧酸衍生物(例如二氟尼柳(diflunisal)和氟苯柳(flufenisal));昔康类(oxicams)(例如伊索昔康(isoxicam)、吡罗昔康(piroxicam)、舒多昔康(sudoxicam)和替诺昔康(tenoxicam));水杨酸盐/酯类(例如乙酰水杨酸(acetylsalicylic acid)和柳氮磺吡啶(sulfasalazine));及布他酮类(pyrazolone)(例如阿扎丙宗(apazone)、苄哌吡酮(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羟布宗(oxyphenbutazone)和保泰松(phenylbutazone));
COX II抑制剂,例如洛芬昔布(rofecoxib)及塞来昔布(celecoxib);干扰素β制剂(例如干扰素β-1a或干扰素β-1b);
以及某些其他化合物,例如5-氨基水杨酸及其前药和可药用盐。
还已证明二甲双胍具有抗炎性质[参见Haffner等,Diabetes54:1566-1572(2005)]且因此也可用于本发明的情形。
以下实例证明了本发明的某些特定实施方案。除非另外详细描述,否则使用本领域技术人员公知和常规的标准技术进行以下实施例。应了解,这些实施例仅用于说明性目的且不应旨在对本发明的条件或范畴的完全限定。因此,其不应被视为以任何方式限制本发明的范围。
实施例中采用的缩写包括:
NMP:N-甲基吡咯烷酮
DCM:二氯甲烷
DMF:N,N-二甲基甲酰胺
HATU:2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐/酯
DIPEA:二异丙基乙胺
EtOH:乙醇
Et2O:乙醚
8Ado:8-氨基-3,6-二氧杂辛酰基
8Aoc:8-氨基辛酰基
TFA:三氟乙酸
MeCN:乙腈
HPLC:高效液相色谱
MS:质谱
IBMX:3-异丁基-1-甲基黄嘌呤
BSA:牛血清白蛋白
cAMP:环单磷酸腺苷
DMEM:达尔伯克氏改良的伊格尔培养基(Dulbecco’s Modified EagleMedium)
FCS:胎牛血清
HEPES:N-2-羟乙基哌嗪-N′-2-乙烷磺酸
p-ERK:磷酸化细胞外调节激酶
PBS:磷酸盐缓冲盐水
Boc:叔丁氧羰基
NEP:N-乙基吡咯烷酮
利拉鲁肽:[Arg34,Lys26(十六酰基-异Glu)]GLP-1(7-37)
化合物的合成
材料及方法
除非另外说明,否则下文采用的试剂和溶剂可以标准实验室试剂或分析级别商业获得,且不经进一步纯化使用。
本发明之肽缀合物合成的一般方法
使用标准Fmoc化学在CEM Liberty肽合成器上进行固相肽合成。使用之前将TentaGelTM S Ram树脂(1g;0.25mmol/g)于NEP(10ml)中膨胀并使用DCM和NEP在管与反应容器之间转移。适当时使用假脯氨酸(其为用来最小化肽合成期间之聚集的二肽,例如Fmoc-Phe-Thr(ψ-Me,Me-Pro)-OH和Fmoc-Asp-Ser(ψ-Me,Me-Pro)-OH),且采用非天然氨基酸(即Fmoc-8Ado-OH)而不对一般方法进行任何变化。
偶联:
将NEP/DMF/DCM(1∶1∶1;0.2M;5ml)中的Fmoc-氨基酸连同HATU/DMF(0.5M;2ml)和DIPEA/NEP(2.0M;1ml)一起添加至CEM Discover微波装置中的树脂中。将偶联混合物加热至75℃并持续5分钟,同时使氮气鼓泡穿过混合物。随后用NEP(4×10ml)洗涤树脂。
去保护:
向树脂中添加哌啶/NEP(1/4(表示1份哌啶对4份NEP);10ml)用于初始去保护,并微波加热混合物(40℃;30秒)。抽干反应容器并添加第二份哌啶/NEP(1/4;10ml)且再次加热(75℃;3分钟)。随后用NEP(6×10ml)洗涤树脂。
切割:
用EtOH(3×10ml)和Et2O(3×10ml)洗涤树脂并在室温(r.t.)下干燥至恒重。通过用TFA/TIS/H2O(90/5/5;40mi;2小时;r.t.)处理使粗制肽自树脂切割。在减压下移除大部分TFA,并使粗制肽沉淀且用Et2O洗涤三次,并在室温下干燥至恒重。
纯化及表征:
使用装配有合适柱和级分收集器(fraction collector)且以缓冲液A(0.1%TFA,水溶液)和缓冲液B(0.1%TFA,90%MeCN,水溶液)之梯度运行的PerSeptive Biosystems VISION Workstation,通过制备型反相HPLC将粗制肽纯化至大于90%的纯度。
通过分析型HPLC和MS分析级分,且将相关级分汇集并冻干。通过HPLC和MS表征最终产物。
实施例1:化合物2[Leu14,Lys25(十六酰基-异Glu)]毒蜥外泌肽-4(1-28)-8Ado-8Ado-[Leu4]胃泌素6的合成
在CEM Liberty肽合成器上使用如上所述的TentaGel S Ram树脂(1.13g;0.24mmol/g)和Fmoc化学合成[Leu14]毒蜥外泌肽-4(1-28)-8Ado-8Ado-[Leu4]胃泌素6。在连接点处采用Fmoc-8-氨基-3,6-二氧杂辛酸(Fmoc-8Ado-OH)以及Fmoc-Lys(Dde)-OH进行酰化。
以NMP洗涤(3×2分钟)树脂结合之受保护的线性肽。使用DCM(4ml)中的Boc2O(265mg)和DIPEA(47μl)使固相连接肽之N端经Boc保护且用NMP洗涤(5×2分钟)。随后使用水合肼/NEP(4/96;2×15分钟)切割Dde保护基团,并用NMP(5×2分钟)、DIEA/NMP(1/9;3×5分钟)和NMP(8×2分钟)洗涤树脂。如上所述使用Fmoc-Glu-OtBu和十六酸在CEM Liberty肽合成器上完成合成。
如上所述的来自自树脂切割的肽,并在Gemini-NX柱(5×25cm;10μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物的35ml/分钟流进行纯化。用30%至65%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(9ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(39mg),其经分析型HPLC分析为81%纯。如由MS所确定,质量为4655.53Da(计算值4655.44Da)。
实施例2:化合物6[Cys16(生物素-Mal),Leu14]毒蜥外泌肽-4(1-28)-8Ado-8Ado-[Leu4]胃泌素6的合成
如上所述使用2份TentaGel S Ram树脂(1.12g;0.25mmol/g)和Fmoc化学,使用Fmoc-Phe-Thr(ψ-Me,Me-Pro)-OH和Fmoc-8-氨基-3,6-二氧杂辛酸(Fmoc-8Ado-OH)在CEM Liberty肽合成器上合成[Cys16,Leu14]毒蜥外泌肽-4(1-28)-8Ado-8Ado-[Leu4]胃泌素6。如上所述从树脂(1号部分)切割肽。
1号纯化:在Gemini-NX柱(5×25cm;10μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物之35ml/分钟流纯化来自1号树脂的粗制肽。用30%至65%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(9ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(90mg),其经分析型HPLC分析为68%纯。
2号纯化:在Gemini-NX柱(10mm×25cm;5μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物之4ml/分钟流纯化来自1号纯化的产物。用30%至60%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(2ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(25mg),其经分析型HPLC分析为91%纯。
3号纯化:在Gemini柱(5×25cm;10μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物之35ml/分钟流纯化来自2号树脂的粗制肽。用30%至65%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(9ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(129mg),其经分析型HPLC分析为74%纯。
4号纯化:在Gemini-NX柱(10mm×25cm;5μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物之4ml/分钟流纯化来自2号和3号纯化的组合产物。用30%至55%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(2ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(32mg)(其经分析型HPLC分析为73%纯)及另一白色粉末(100mg)(其经分析型HPLC分析为62%纯)。
5号纯化:在Gemini-NX柱(10mm×25cm;5μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物之4ml/分钟流纯化来自4号纯化的组合产物。用30%至55%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(2ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(30mg),其经分析型HPLC分析为90%纯。如由MS所确定,质量为4320.24Da(计算值为4320.12Da)。
缀合:将来自5号纯化的产物溶解于PBS缓冲液(6ml;pH7.4)中,产生混浊溶液(pH6.2)。将生物素-马来酰亚胺(10.7mg)溶解于DMSO(1.1ml)中并添加至肽溶液中。通过分析型HPLC监测反应且在3小时后使用Gemini-NX柱(10mm×25cm;5μm;C18)用缓冲液A(0.1%TFA;水溶液)和缓冲液B6055%缓冲液B之混合物的4ml/分钟流纯化47分钟,并用级分收集器收集级分(2ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(18mg),其经分析型HPLC分析为84%纯。如由MS所确定,质量为4771.35Da(计算值为4771.31Da)。实施例3:化合物9[Glu9,Leu14,Phe25,Tyr13]毒蜥外泌肽-4(1-27)-QQ-[Leu4]胃泌素6的合成
如上所述使用TentaGel S Ram树脂(1.10g;0.25mmol/g)和Fmoc化学,使用Fmoc-Phe-Thr(Ψ-Me,Me-Pro)-OH在CEM Liberty肽合成器上合成肽。该肽从如上所述的树脂切割。在Gemini-NX柱(5×25cm;10μm;C18)上用缓冲液A(0.1%TFA;水溶液)和缓冲液B(0.1%TFA;90%MeCN;水溶液)混合物的35ml/分钟流纯化粗制肽。从20%至50%缓冲液B的线性梯度洗脱产物47分钟,并用级分收集器收集级分(9ml)。通过分析型HPLC和MS分析相关级分,汇集并冻干以产生白色粉末(137mg),其经分析型HPLC分析为78%纯。如由MS所确定,质量为4208.11Da(计算值为4208.09Da)。
实施例4:通过本发明的肽缀合物对GLP-1受体和胃泌素CCK-B受体的体外活化(EC50)
材料及方法
人GLP-1受体(GLP-1R)效力测定:
通过使用来自Perkin-Elmer的FlashPlateTM cAMP试剂盒,在由GLP-1(7-36)、毒蜥外泌肽-4(1-39)或本发明的缀合物刺激受体后测量cAMP的诱导来评估本发明之肽缀合物的体外作用。简要地说,将表达人GLP-1R(通过转染GLP-1R的cDNA和选择稳定克隆而产生的稳定细胞系)的HEK293细胞以每孔40,000个细胞接种于涂布有0.01%聚L-赖氨酸的96孔微量滴定板中,并在100μl生长培养基[DMEM、10%FCS、青霉素(100IU/ml)、链霉素(100μg/ml)]中的培养物中生长1天。在分析当日,移除生长培养基并用200μlTyrode缓冲液[Tyrode盐(9.6g/l)、10mM HEPES、pH7.4]洗涤细胞一次。在37℃下,将细胞在含有浓度递增的测试化合物、100μM IBMX和0.1%BSA的100μl Tyrode缓冲液中孵育15分钟。通过添加25μl0.5M HCl中止反应并在冰上孵育60分钟。关于其他方法详情,参见WO2008/152403。
CCK-B受体(CCK-B R)效力测定:
通过在稳定表达人CCK-B R(高亲和力胃泌素受体;经由转染CCK-B R的cDNA和选择稳定克隆而产生的稳定细胞系)的HEK293细胞中测量p-ERK(使用AlphaScreenTM SureFire p-ERK测定)来估计本发明之肽缀合物和对照胃泌素17类似物[Leu15]胃泌素17的体外作用。如下进行胃泌素受体效力测定(AlphaScreenTM SureFire p-ERK测定):在第1天,将CCK-B R表达细胞以每孔20,000个细胞接种于涂布有聚D-赖氨酸之96孔盘中的100μl生长培养基[DMEM、10%FCS、青霉素(100IU/ml)、链霉素(100μg/ml)]中。将细胞在培养箱(37℃,5%CO2)中孵育2天。随后将生长培养基更换为每孔80μl无血清培养基[DMEM、青霉素(100IU/ml)、链霉素(100μg/ml)]并继续在培养箱中将细胞孵育过夜。在分析当日,在20μl不含血清的培养基中添加递增浓度的化合物,并将细胞在室温下孵育5分钟。通过快速倒转板丢弃刺激培养基,并每孔添加60μl1×裂解缓冲液(来自SureFire测定试剂盒)。关于更多详情,参见WO2011/134471。
以上述测定(即,人GLP-1R活化效力、人CCK-BR活化效力)中测试本发明的肽缀合物。
在人GLP-1受体(hGLP-1R)活化测定中使用毒蜥外泌肽-4(1-39)作为阳性对照,且在人CCK-B受体(hCCK-B R)活性测定中使用h[Leu15]胃泌素17作为阳性对照。
结果(EC50值,以nM计)总结于下表1中。
表1.本发明的化合物(肽缀合物)在hGLP-1R和hCCK-B R活化中的体外活性(EC50,nM)
结果
上表1中总结的结果表明,本发明的肽缀合物为所关注两种受体的有效激动剂,且其展示极其类似的活性水平。
实施例5:选定化合物在小鼠内的药物代谢动力学(PK)
方法
对C57Bl L/6J小鼠给予100nmol/kg单一皮下剂量的每种待测肽。在5和30分钟后及在1、2、4、6、16和24小时后取血液样品。在每个时间点从两只小鼠取样品。血液采样后立即通过颈脱位法(cervicaldislocation)对小鼠施行安乐死。在固相体取(solid phase extraction,SPE)之后,通过液相色谱质谱法(LC-MS/MS)分析血浆样品。
表2.对小鼠皮下施用100nmol/kg后的T1/2
化合物 | T1/2(小时) |
7 | 6.2 |
12 | 5.0 |
18 | 4.1 |
19 | 2.4 |
22 | 8.2 |
23 | 6.7 |
实施例6:三周体内db/db小鼠研究
db/db小鼠模型先前已用来评估潜在治疗候选物的β细胞保存效果[Rolin,B.等,Am.J.Physiol.Endocrinol.Metab.283:E745-E752(2002)]。若干研究已证明胰胰岛素含量与β细胞质量之间的相关性[Rolin,B.等(在上述引文中);Suarez-Pinzon,W.L.等,Diabetes54:2596-2601(2005);Suarez-Pinzon W.L.等,Diabetes57:3281-3288(2008)]。
处理
将db/db小鼠根据HbA1c水平分为各种处理组。每天一次以皮下(SC)注射处理小鼠总共21天。注射体积为5ml/kg。研究期间,每日记录体重(BW)且用来施用体重折算之肽的剂量。
OGTT
在第16天,对动物进行口服葡萄糖耐量测试。在施用葡萄糖之前(t=0时,基线)和施用葡萄糖达2小时后测量血糖。
终止
终止时,测量血糖水平,并分析血液样品的HbA1c水平。
测量
通过固定葡萄糖氧化酶法(Elite Autoanalyser,Bayer,Denmark)确定全血糖浓度(mM)。使用Cobas c111分析器(Roche Diagnostics,Mannheim,Germany)分析血液样品的HbA1c。
结果
毒蜥外泌肽-胃泌素双重激动剂化合物18和化合物23二者在处理16天之后都使空腹血糖水平降低。化合物18使空腹血糖水平降低的程度大于化合物23。两种化合物在处理3周后都使HbA1c的血浆水平降低,两种化合物之间无显著差异(非成对双尾t检验)。
化合物18和化合物23二者在第16天的口服葡萄糖激发(oral glucosechallenge)后都使得葡萄糖浓度曲线下的面积(AUC)降低(表3),其中化合物18使得葡萄糖浓度降低的程度大于化合物23。
最后,化合物18与化合物23二者在3周研究进程期间都使得体重增长降低(表3),其中化合物18使得体重增长降低的程度大于化合物23。
表3.三周体内db/db研究结果
表3的图例:
Δ-HbA1c:在对db/db小鼠处理21天后,SC施用载剂、化合物18(100nmol/kg)和化合物23(100nmol/kg)对Δ-HbA1c(%)水平(研究开始时的HbA1c水平减去终止时的HbA1c水平)的影响。数据以带有SEM的平均值给出(每组n=11)。(-)表示Δ-HbA1c水平在0.5%之上,(+)表示Δ-HbA1c水平在0.25%与0.5%之间,(++)表示Δ-HbA1c水平在0%与0.25%之间,(+++)表示Δ-HbA1c水平低于0%。
OGTT曲线下的面积(AUC):通过在处理16天后的db/db小鼠中的葡萄糖负荷后的曲线下面积(AUC)所测量的SC施用载剂、化合物18(100nmol/kg)和化合物23(100nmol/kg)对葡萄糖耐量的影响。数据以带有SEM的平均值给出(每组n=11)。(-)表示OGTT AUC大于3000mM*分钟,(+)表示OGTT AUC在2000与3000mM*分钟之间,(++)表示OGTT AUC在1000与2000M*分钟之间,(+++)表示OGTT AUC低于1000mM*分钟。
Δ-BW:在对db/db小鼠处理21天后,SC施用载剂、化合物18(100nmol/kg)和化合物23(100nmol/kg)对Δ-BW(g)水平(研究开始时的BW减去终止时的BW)的影响。数据以带有SEM的平均值给出(每组n=9-11)。(-)表示ΔBW大于8g,(+)表示ΔBW在6与8g之间,(++)表示ΔBW在4与6g之间,(+++)表示ΔBW低于4g。
空腹BG:在对db/db小鼠处理16天后,SC施用载剂、化合物18(100nmol/kg)和化合物23(100nmol/kg)对空腹血糖(mM)水平的影响。数据以带有SEM的平均值给出(每组n=11)。(-)表示空腹BG大于12mM,(+)表示空腹BG在8与12mM之间,(++)表示空腹BG在6与8mM之间,(+++)表示空腹BG低于6mM。
实施例7:体内db/db小鼠研究:4周处理后接着2周药物假期
处理
将db/db小鼠根据HbA1c水平分为多个处理组。每天一次以皮下(SC)注射处理小鼠总计4周,其后对其以载剂给药2周。注射体积为5ml/kg。研究期间,每日记录体重(BW)且用来施用体重折算之肽的剂量。
OGTT
在3周和5周后,对动物进行口服葡萄糖耐量测试。在施用葡萄糖之前(t=0时,基线)和施用葡萄糖达2小时后测量血糖。
测量
通过固定葡糖氧化酶方法(Elite Autoanalyser,Bayer,Denmark)确定全血糖浓度(mM)。
结果
毒蜥外泌肽-胃泌素双重激动剂化合物18与载剂相比在处理3周后使空腹血糖水平降低。化合物18使空腹血糖水平降低的程度大于等摩尔剂量的利拉鲁肽,参见图1。4周处理接着1周药物假期(载剂给药)之后,化合物18与载剂相比使空腹血糖水平显著降低。化合物18使空腹血糖水平降低的程度大于等摩尔剂量的利拉鲁肽,参见图2。
化合物18在处理3周后于口服葡萄糖激发后使得葡萄糖浓度曲线下面积(AUC)降低,其中化合物18使得葡萄糖浓度曲线(AUC)降低的程度大于利拉鲁肽,参见图3。
4周处理接着1周药物假期(载剂给药)之后,在口服葡萄糖激发后,化合物18与载剂相比使葡萄糖浓度曲线下面积(AUC)显著降低,参见图4。化合物18使葡萄糖浓度曲线(AUC)降低的程度大于等摩尔剂量的利拉鲁肽。
最后,化合物18在4周研究进程期间使得体重增长降低,其中化合物18使得体重降低的程度大于等摩尔剂量的利拉鲁肽,参见图5。
实施例8:体内ZDF大鼠研究:6周处理
处理
将ZDF大鼠根据HbA1c水平分为各种处理组。每天两次以皮下(SC)注射处理大鼠总计6周。注射体积为5ml/kg。研究期间,每日记录体重(BW)且用于施用体重折算之肽的剂量。
OGTT
5周后,对动物进行口服葡萄糖耐量测试。在施用葡萄糖之前(t=0时,基线)和施用葡萄糖达2小时后测量血糖。
终止
终止时,分析血液样品的HbA1c水平。
测量
通过固定葡糖氧化酶方法(Elite Autoanalyser,Bayer,Denmark)确定全血糖浓度(mM)。
使用Cobas c111分析器(Roche Diagnostics,Mannheim,Germany)分析血液样品的HbA1c。
结果
毒蜥外泌肽-胃泌素双重激动剂化合物18与载剂相比在处理5周后使空腹血糖水平降低。化合物18使空腹血糖水平降低的程度大于等摩尔剂量的利拉鲁肽,参见图6。
5周处理后,在口服葡萄糖激发后,化合物18使葡萄糖浓度曲线下面积(AUC)降低,其中化合物18使葡萄糖浓度曲线下面积(AUC)降低的程度大于利拉鲁肽,参见图7。
6周处理后,化合物18与载剂相比使得HbA1c水平显著降低。化合物18使得HbA1c水平降低的程度大于等摩尔剂量的利拉鲁肽,参见图8。
Claims (48)
1.具有式I的肽缀合物或者其可药用盐或溶剂合物:
R1-Za-La-Ya-R2 (I)
其中
R1为H、C1-4烷基、乙酰基、甲酰基、苯甲酰基或三氟乙酰基;并且
R2为OH或NH2;
Za为具有式Ia的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-Z13-Z14-Glu-Z16-Glu-Ala-Val-Z20-Leu-Phe-Ile-Z24-Z25-Leu-Z27-Z28(Ia)
其中
Z9选自Asp和Glu;
Z12选自Lys、Arg和Orn;
Z13选自Gln和Tyr;
Z14选自Met和Leu;
Z16选自Glu、Arg、Orn、Cys和Lys;
Z20选自Arg、Lys和Orn;
Z24选自Arg、Orn、Lys和Glu;
Z25选自Trp、Lys、Cys和Phe;
Z27选自Lys、Arg和Orn;并且
Z28选自Asn和Asp或不存在;
La为具有式Ib的肽序列
L1-L2-L3-L4 (Ib)
其中
L1选自Orn、8Ado、Cys、Lys和Gln或不存在;
L2选自Orn、8Ado、Cys、Lys和Gln或不存在;
L3选自Orn、8Ado、Cys、Lys和Gln或不存在;并且
L4选自Orn、8Ado、Cys、Lys和Gln或不存在;
Ya为具有式Ic的肽序列
Y12-Y13-Y14-Y15-Asp-Y17 (Ic);
其中
Y12选自Tyr和Ala或不存在;
Y13选自Gly和Ala或不存在;
Y14选自Trp、1Nal和Phe;
Y15选自Met、Leu、Nle、Thr和Phe;并且
Y17选自Phe和3-(3-吡啶基)-丙氨酸;
其中在式Ia和Ib中Lys、Orn或Cys中的至少一个进一步与亲脂性和/或生物素基取代基缀合和/或聚乙二醇化。
2.根据权利要求1所述的肽缀合物或者其可药用盐或溶剂合物,其中
Za为具有式IIa的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Lys-Z13-Z14-Glu-Z16-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28(IIa)
其中
Z9选自Glu和Asp;
Z13选自Gln和Tyr;
Z14选自Met和Leu;
Z16选自Glu、Cys和Lys;
Z25选自Lys、Phe、Cys和Trp;并且
Z28选自Asn和Asp或不存在;
La为具有式Ib的肽序列;
Ya为具有式IIc的肽序列
Tyr-Gly-Trp-Y15-Asp-Phe(IIc)
其中
Y15选自Leu和Thr;并且
其中在式IIa或式IIb的位置Z16或Z25中Lys或Cys中的至少一个进一步与亲脂性和/或生物素基取代基缀合和/或聚乙二醇化。
3.根据权利要求1或权利要求2所述的肽缀合物或者其可药用盐或溶剂合物,其中式I的肽序列选自
H-HGEGTFTSDLSKQLEEEAVRLFIEWLKN-8Ado-K(十六烷酰基-异Glu)-8Ado-YGWLDF-NH2
H-HGEGTFTSDLSKQLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKN-8Ado-8Ado-YGWLDF-NH2
H-HGEGTFTSDLSKQLE-K(十六烷酰基-异Glu)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2
H-HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-C(生物素-Mal)-8Ado-YGWLDF-NH2
H-HGEGTFTSDLSKQLEEEAVRLFIE-C(生物素-Mal)-LKN-8Ado-8Ado-YGWLDF-NH2
H-HGEGTFTSDLSKQLE-C(生物素-Mal)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-8Ado-YGWLDF-NH2和
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-QQYGWLDF-NH2
4.具有式III的肽缀合物或者其可药用盐或溶剂合物
R1-Zb-Lb-Yb-R2(III)
其中
R1为H、C1-4烷基、乙酰基、甲酰基、苯甲酰基或三氟乙酰基;
R2为OH或NH2;
Zb为具有式IIIa的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Z25-Leu-Lys-Z28(IIIa)
其中
Z25选自Phe和Trp;并且
Z28选自Asn和Asp或不存在;
Lb为具有式IIIb的肽序列
L5-L6-L7-L8(IIIb)
其中
L5选自8Ado、8Aoc、Ala、Gly和Gln或不存在;
L6选自8Ado、8Aoc、Ala、Gly和Gln或不存在;
L7选自8Ado、8Aoc、Ala、Gly和Gln或不存在;并且
L8选自8Ado、8Aoc、Ala、Gly和Gln或不存在;
Yb为具有式IIIc的肽序列
Y10-Y11-Tyr-Gly-Trp-Y15-Asp-Phe(IIIc)
其中
Y10为Glu或不存在;
Y11为Ala或不存在;并且
Y15选自Leu和Thr;
前提为式III不是
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKYGWLDF-NH2;和
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-YGWLDF-NH2。
5.根据权利要求4所述的肽缀合物或者其可药用盐或溶剂合物,其中
Zb为具有式IVa的肽序列
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Asn(IVa)
其中
Z25选自Phe和Trp;并且
Lb为具有式IIIb的肽序列;
Yb为具有式IVc的肽序列
Tyr-Gly-Trp-Y15-Asp-Phe(IVc)
其中
Y15选自Leu和Thr。
6.根据权利要求4或权利要求5所述的肽缀合物或者其可药用盐或溶剂合物,其中式III的肽序列选自
H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-QQYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Aoc-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKD-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKEAYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六烷酰基-异Glu)-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六烷酰基-异Glu)-WLDF-NH2;
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKNYGWLDF-NH2;
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKNWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六烷酰基-异Glu)-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六烷酰基-异Glu)-WLDF-NH2;
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKYGWLDF-NH2;
H-HGEGTFTSELSKYLE-K(十六烷酰基-异Glu)-EAVRLFIEFLKWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKQQYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LK-Orn-Orn-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKNYGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六烷酰基-异Glu)-LKDYGWLDF-NH2;
H-HGEGTFTSDLSKQLEEEAVRLFIEC(PEG5K)LKN-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG10K)LK-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG20K)LK-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG40K)LK-8Ado-8Ado-YGWLDF-NH2;
H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNYGWTDF-OH;和
H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWTDF-NH2。
7.根据权利要求1至6中任一项所述的肽缀合物或者其可药用盐或溶剂合物,其中Za或Zb与天然钝尾毒蜥(Heloderma suspectum)的毒蜥外泌肽-4具有至少75%、80%、85%、90%或95%的同一性。
8.根据权利要求1至6中任一项所述的肽缀合物,其中Ya或Yb与天然人胃泌素17和/或胃泌素6具有至少70%、80%、83%、85%、90%、94%或95%的同一性。
9.根据权利要求1至8中任一项所述的肽缀合物或者其可药用盐或溶剂合物,其用作药物。
10.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物,其用作用于治疗选自以下之疾病或病症的药物:1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、糖耐量减低(IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常、动脉硬化(例如动脉粥样硬化)、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭。
11.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物,其用作用于在有此需要的对象中诱导胰β细胞和/或胰岛新生的药物。
12.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物,其用作用于在有此需要的对象中诱导胰岛β细胞存活的药物。
13.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物,其用作用于在有此需要的对象中预防胰岛中β细胞凋亡和/或坏死的药物。
14.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物,其用作用于在有此需要的对象中诱导胰岛中β细胞增殖的药物。
15.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物,其用作用于在有此需要的对象中诱导胰岛中β细胞新生、胰岛新生、β细胞存活、β细胞增殖和/或预防β细胞凋亡和/或坏死之任意组合的药物。
16.根据权利要求9至15中任一项所述的肽缀合物或者其可药用盐或溶剂合物,其中所述对象是人。
17.用于在有此需要的对象中治疗选自以下之疾病或病症的方法:
1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、糖耐量减低(IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常、动脉硬化(例如动脉粥样硬化)、大血管疾病、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭,
所述方法包括向所述有需要的对象施用治疗有效量的根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物。
18.用于在有此需要的对象中预防选自以下之疾病或病症的方法:
1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、糖耐量减低(IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常、动脉硬化(例如动脉粥样硬化)、大血管疾病、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭,
所述方法包括向所述有需要的对象施用治疗有效量的根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物。
19.根据权利要求18所述的方法,其中所述对象是人。
20.药物组合物,其包含根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物以及可药用载体、赋形剂或载剂。
21.根据权利要求19所述的药物组合物,其用于治疗1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、糖耐量减低(IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常、动脉硬化(例如动脉粥样硬化)、大血管疾病、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭。
22.根据权利要求19所述的药物组合物,其用于预防1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、糖耐量减低(IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常、动脉硬化(例如动脉粥样硬化)、大血管疾病、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭。
23.根据权利要求19所述的药物组合物,其用于预防体重增长或促进体重减轻。
24.根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物,其用于选自以下的方法:改善循环葡萄糖水平、改善葡萄糖耐量和/或改善循环胆固醇水平、降低循环LDL水平、提高HDL/LDL比值及其组合。
25.根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物,其用于治疗或预防由体重过重所引起或以体重过重为特征之病状的方法。
26.根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物用于在有此需要的个体中预防体重增长或促进体重减轻的用途。
27.根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物在有此需要的个体中改善循环葡萄糖水平、葡萄糖耐量和/或循环胆固醇水平、降低循环LDL水平和/或提高HDL/LDL比值之方法中的用途。
28.根据权利要求1至27中任一项所述的肽缀合物或者其可药用盐或溶剂合物、用途或方法,其中所述化合物作为与质子泵抑制剂或者用于治疗或预防糖尿病、肥胖、血脂异常或高血压之药剂的组合治疗的一部分来施用。
29.根据权利要求28所述的肽缀合物或者其可药用盐或溶剂合物、用途或方法,其中所述用于治疗或预防糖尿病的药剂是二甲双胍、磺酰脲类、格列奈类、DPP-IV抑制剂、格列酮类、胰岛素或胰岛素类似物。
30.根据权利要求28所述的肽缀合物或者其可药用盐或溶剂合物、用途或方法,其中所述用于治疗或预防肥胖的药剂是胰高血糖素样肽受体1激动剂、肽YY或其类似物、大麻素受体1拮抗剂、脂肪酶抑制剂、黑皮质素受体4激动剂或黑色素聚集激素受体1拮抗剂。
31.根据权利要求28所述的肽缀合物或者其可药用盐或溶剂合物、用途或方法,其中所述用于治疗或预防高血压的药剂是血管紧张素转化酶抑制剂、血管紧张素II受体阻断剂、利尿剂、β-阻断剂或钙通道阻断剂。
32.根据权利要求28所述的肽缀合物或者其可药用盐或溶剂合物、用途或方法,其中所述用于治疗或预防血脂异常的药剂是他汀类、贝特类、烟酸类和/或胆固醇吸收抑制剂。
33.根据权利要求28所述的肽缀合物或者其可药用盐或溶剂合物、用途或方法,其中已知类型的所述质子泵抑制剂(即具有作为H+/K+-ATP酶抑制剂之药理活性的药剂)包括但不限于苯并咪唑衍生物类型或咪唑并吡啶衍生物类型的药剂。
34.以合成方式制造根据权利要求1至16中任一项所述之肽缀合物的方法。
35.以重组方式制造根据权利要求1至16中任一项所述之肽缀合物或者其可药用盐或溶剂合物缀合物的方法。
36.根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物在有此需要的个体中的选自以下方法中的用途:改善循环葡萄糖水平、改善葡萄糖耐量和/或改善循环胆固醇水平、降低循环LDL水平、提高HDL/LDL比值及其组合,其中使用药物假期给药方案。
37.用于制造肽缀合物或者其可药用盐或溶剂合物或者根据前述权利要求中任一项所述的方法。
38.药物组合物,所述药物组合物包含根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物,其与一种或更多种根据权利要求1至16所述的肽缀合物或者其可药用盐或溶剂合物连同可药用载体、赋形剂或载剂相组合。
39.装置,其包含至少一种根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物,所述装置用于向对象递送所述肽缀合物或者其可药用盐或溶剂合物。
40.试剂盒,其包含至少一种根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物以及包装或使用说明。
41.根据权利要求1至16中任一项所述的肽缀合物或者其可药用盐或溶剂合物用于制备药物的用途。
42.根据权利要求9所述的肽缀合物或者其可药用盐或溶剂合物的用途,其中所述药物用于在有此需要的对象中治疗或预防选自以下的疾病或病症:
1型糖尿病、2型糖尿病、前驱糖尿病、胰岛素抗性综合征、糖耐量减低(IGT)、与血糖水平升高相关的疾病状态、高血糖、高血压、致动脉粥样化的血脂异常、动脉硬化(例如动脉粥样硬化)、大血管疾病、冠心病、外周动脉疾病、卒中、微血管疾病、胃病、代谢综合征、癌症(例如结肠癌)、炎性肠病(IBD)、肠易激综合征(IBS)、糖尿病性神经病、糖尿病性视网膜病、糖尿病性肾病和肾衰竭。
43.根据权利要求41所述的肽缀合物或者其可药用盐或溶剂合物的用途,其中所述药物用于在有此需要的对象中诱导胰β细胞和/或胰岛新生。
44.根据权利要求41所述的肽缀合物或者其可药用盐或溶剂合物的用途,其中所述药物用于在有此需要的对象中改善胰岛β细胞的存活率。
45.根据权利要求41所述的肽缀合物或者其可药用盐或溶剂合物的用途,其中所述药物用于在有此需要的对象中预防胰岛中β细胞凋亡和/或坏死。
46.根据实施方案权利要求41所述的肽缀合物或者其可药用盐或溶剂合物的用途,其中所述药物用于在有此需要的对象中诱导胰岛β细胞的增殖。
47.根据实施方案41至46中任一项所述的肽缀合物或者其可药用盐或溶剂合物的用途,其中所述对象是人。
48.根据权利要求21所述的肽缀合物或者其可药用盐或溶剂合物,其中所述由体重过重所引起或以体重过重为特征的病状选自肥胖、病态肥胖、肥胖相关炎症、肥胖相关胆囊疾病、肥胖诱发的睡眠呼吸暂停、代谢综合征、前驱糖尿病,所述方法包括向所述对象施用治疗有效量的根据权利要求23所述的肽缀合物或者其可药用盐或溶剂合物。
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CN109248323A (zh) * | 2017-07-14 | 2019-01-22 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
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CN109195983A (zh) * | 2016-03-10 | 2019-01-11 | 深圳君圣泰生物技术有限公司 | 胰岛新生多肽和类似物的缀合物及其方法 |
CN109195983B (zh) * | 2016-03-10 | 2022-05-17 | 深圳君圣泰生物技术有限公司 | 胰岛新生多肽和类似物的缀合物及其方法 |
CN109248323A (zh) * | 2017-07-14 | 2019-01-22 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
CN109248323B (zh) * | 2017-07-14 | 2023-09-08 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
CN109331173A (zh) * | 2018-12-17 | 2019-02-15 | 中国医学科学院医学实验动物研究所 | 胃泌素-二氧化硅微球及其用途 |
CN109331173B (zh) * | 2018-12-17 | 2021-05-07 | 中国医学科学院医学实验动物研究所 | 胃泌素-二氧化硅微球及其用途 |
CN112759640A (zh) * | 2020-12-09 | 2021-05-07 | 江苏师范大学 | 一类glp-1/胃泌素受体双重激动剂及其应用 |
CN112759640B (zh) * | 2020-12-09 | 2023-09-08 | 江苏师范大学 | 一类glp-1/胃泌素受体双重激动剂及其应用 |
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EA028951B1 (ru) | 2018-01-31 |
JP6359972B2 (ja) | 2018-07-18 |
EP2773377B1 (en) | 2020-07-08 |
US9861706B2 (en) | 2018-01-09 |
EP2773377A1 (en) | 2014-09-10 |
CN104144704B (zh) | 2018-03-23 |
US20140336107A1 (en) | 2014-11-13 |
AU2012331053A1 (en) | 2014-05-29 |
KR20140100947A (ko) | 2014-08-18 |
MX2014005351A (es) | 2014-05-28 |
WO2013064669A1 (en) | 2013-05-10 |
US20160082118A1 (en) | 2016-03-24 |
EA028951B9 (ru) | 2018-05-31 |
TW201326194A (zh) | 2013-07-01 |
EA201490790A1 (ru) | 2014-10-30 |
BR112014010780A2 (pt) | 2017-04-25 |
CA2853884A1 (en) | 2013-05-10 |
AR088636A1 (es) | 2014-06-25 |
US9259477B2 (en) | 2016-02-16 |
JP2015502918A (ja) | 2015-01-29 |
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