CN102170895A - 葡萄糖依赖性促胰岛素多肽类似物 - Google Patents
葡萄糖依赖性促胰岛素多肽类似物 Download PDFInfo
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Abstract
本发明提供了一系列新的葡萄糖依赖性促胰岛素多肽的类似物,包含所述化合物的药物组合物,及所述化合物作为GIP受体激动剂或拮抗剂用于治疗GIP受体介导的疾病例如非胰岛素依赖性糖尿病和肥胖中的用途。
Description
发明领域
本发明涉及以下领域:葡萄糖依赖性促胰岛素多肽的新类似物,包含所述化合物的药物组合物,及所述化合物作为GIP受体激动剂或拮抗剂在治疗GIP受体介导的病症例如非胰岛素依赖性糖尿病和肥胖中的用途。
技术背景
葡萄糖依赖性促胰岛素多肽(“GIP”,又称“抑胃肽”:SEQ ID NO:1)是由小肠的肠内分泌K细胞应答口服营养摄入分泌的42个残基的肽。GIP抑制胃酸的分泌,有研究显示在口服葡萄糖摄入后,GIP是胰腺β细胞分泌胰岛素的有效刺激物(“肠降血糖素效应”)(Creutzfeldt,W.,等人,1979,Diabetologia,16:75-85)。
葡萄糖和其他营养物摄入引起的胰岛素释放归因于激素和神经因子二者(Creutzfeldt,W.,等人,1985,Diabetologia,28:565-573)。已经提议了几种胃肠道调节肽作为肠降血糖素,在这些候选肽中,只有GIP和胰高血糖素样肽1(“GLP-1”)似乎满足作为餐后胰岛素释放的生理刺激物的要求(Nauck,等人,1989,J.Clin.Endorinol.Metab.,69:654-662)。有研究显示GIP和GLP-1的组合效应足以解释肠胰岛轴的完整肠降血糖素效应(Fehmann,H.C.,等人,1989,FEBS Lett.,252:109-112)。
如本领域技术人员所熟知的,GIP有多种和大量已知和潜在用途。因此,施用本发明化合物用于引发激动剂效应可具有和GIP自身相同的效应和用途。这些GIP的多种用途可总结如下:治疗疾病,所述疾病选自1型糖尿病、2型糖尿病(Visboll,T.,2004,Dan.Med.Bull.,51:364-70)、胰岛素抗性(WO 2005/082928)、肥胖(Green,B.D.,等人,2004,CurrentPharmaceutical Design,10:3651-3662)、代谢紊乱(Gault,V.A.,等人,2003,Biochem.Biophys.Res.Commun.,308:207-213)、中枢神经系统疾病、神经变性疾病、充血性心力衰竭、低血糖和期望降低食物摄取和减轻体重的疾病。在胰岛中,GIP不仅急性提高胰岛素分泌,而且通过提高胰岛素原的转录和翻译刺激胰岛素的产生(Wang,等人,1996,Mol.Cell.Endocrinol.,116:81-87)并提高胰腺β细胞的生长和存活(Trumper,等人,2003,Diabetes,52:741-750)。除了作用于胰腺以提高胰岛素分泌,GIP还直接作用于胰岛素靶组织以降低血浆葡萄糖:提高脂肪(Eckel,等人,1979,Diabetes,28:1141-1142)和肌肉(O’Harte,等人,1998,J.Endocrinol.,l56:237-243)中的葡萄糖摄入,并抑制肝葡萄糖产生(Elahi,D.,等人,1986,Can.J.Physiol.Pharmacol.,65:A18)。
此外,依照本发明的GIP受体拮抗剂抑制、阻断或降低动物肠内的葡萄糖吸收。依照此发现,包含GIP拮抗剂的治疗组合物可用于非胰岛素依赖性糖尿病患者以提高哺乳动物例如人对口服葡萄糖的耐受性,并通过抑制、阻断或降低哺乳动物肠内的葡萄糖吸收预防、抑制或减轻肥胖。
然而,因为未经修饰的GIP在体内约2分钟的短半衰期(Said和Mutt,1970,Science,169:1217-1218),其在治疗中的应用是受限的。在血清中,由二肽基肽酶(“DPPIV”)降解两种肠降血糖素GIP和GLP-1。提高GIP的蛋白质水解稳定性不仅保留GIP对其受体的活性,更重要的,还会避免GIP片段的产生,这些片段中的一部分起GIP受体拮抗剂的作用(Gault,等人,2002,J.Endocrinol.,175:525-533)。已报导的修饰包括对GIP N-端的保护以避免经DPPIV的蛋白质水解,所述修饰包括N-端酪氨酸的修饰(O’Harte,等人,2002,Diabetologia,45:1281-1291)、2位丙氨酸的突变(Hinke,等人,2002,Diabetes,51:656-661)、3位谷氨酸的突变(Gault,等人,2003,Biochem.Biophys.Res.Commun.,308:207-213)和13位丙氨酸的突变(Gault,等人,2003,Cell Biol.International,27:41-46)。
下面已提交的专利申请涉及GIP类似物对多种靶器官功能的效应及它们作为治疗剂的潜在用途:
PCT公开WO 00/58360公开了刺激胰岛素释放的GIP肽基类似物。特别的,此申请公开了包含GIP(1-42)N-端至少15个氨基酸残基的特定肽基类似物,例如恰好包含位于1、2和3位的1个氨基酸取代或修饰的GIP类似物,例如[Pro3]GIP(1-42)。
PCT公开WO 98/24464公开了基本上包含对应GIP序列7-30位的24个氨基酸多肽的GIP拮抗剂,治疗非胰岛素依赖性糖尿病的方法和提高非胰岛素依赖性糖尿病患者的葡萄糖耐受性的方法。
PCT公开WO 03/082898公开了GIP的C-端截短片段和N-端修饰的类似物,以及具有减少的肽键或在靠近DPPIV特异性切割位点的氨基酸有所改变的多种GIP类似物。此申请还公开了在GIP的潜在受体结合位点间具有不同接头(linker)的类似物。(发明人)声称此申请的化合物在治疗GIP-受体介导的病症例如非胰岛素依赖性糖尿病和肥胖中有作用。
目前存在对改进的GIP类似物的需要,所述类似物在制剂中稳定,由于降低的蛋白质水解敏感性和降低的清除率在体内具有长血浆半衰期,同时保留和GIP受体的结合亲和力以引发相应的激动剂或拮抗剂效应。此外,在如此处说明的本发明化合物的其他治疗作用中,血浆葡萄糖水平的更严格控制可预防长期的糖尿病并发症,因此为患者提供了提高的生活质量。
发明概述
一方面,本发明涉及具有以下通式(I)的GIP肽变体:
(R2R3)-Tyr-Ala-Glu-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-A42-A43-R1,
(I)
其中:
A4是Gly,Acc,Aib,或β-Ala;
A5是Thr,Acc,Aib,或Ser;
A6是Phe,Acc,Aib,Aic,Cha,1Nal,2Nal,2-Pal,3-Pal,4-Pal,(X4,X5,X6,X7,X8)Phe或Trp;
A7是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val;
A8是Ser,Aib,或Thr;
A9是Asp,Aib,或Glu;
A10是Tyr,Acc,Cha,1Nal,2Nal,2-Pal,3-Pal,4-Pal,Phe,或(X4,X5,X6,X7,X8)Phe;
A11是Ser,Acc,Aib,Nle或Thr;
A12是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val;
A13是Ala,Acc,Aib,β-Ala,D-Ala,Gly,或Ser;
A14是Met,Abu,Acc,Aib,Ala,Cha,Ile,Leu,Nle,Phe,Tle,或Val;
A15是Asp,Aib,或Glu;
A16是Lys,Amp,Apc,Arg,hArg,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3);
A17是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val;
A18是His,Amp,Arg,2-Pal,3-Pal,或4-Pal,Phe,或Tyr;
A19是Gln,Aib,或Asn;
A20是Gln,Aib,或Asn;
A21是Asp,Aib,或Glu;
A22是Phe,Acc,Aib,Aic,Cha,1Nal,2Nal,2-Pal,3-Pal,4-Pal,(X4,X5,X6,X7,X8)Phe,或Trp;
A23是Val,Abu,Acc,Aib,Ala,Cha,Ile,Leu,Nle,或Tle;
A24是Asn,Aib,或Gln;
A25是Trp,Acc,Aib,1Nal,2Nal,2-Pal,3-Pal,4-Pal,Phe,或(X4,X5,X6,X7,X8)Phe;
A26是Leu,Acc,Aib,Cha,Ile,Nle,Phe,(X4,X5,X6,X7,X8)Phe或Tle;
A27是Leu,Acc,Aib,Cha,Ile,Nle,Phe,(X4,X5,X6,X7,X8)Phe或Tle;
A28是Ala,Aib,或Acc;
A29是Gln,Aib,Asn,或缺失;
A30是Lys,Amp,Apc,Arg,hArg,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A31是Gly,Acc,Aib,β-Ala,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),His,Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A32是Lys,Amp,Apc,Arg,hArg,Cys,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A33是Lys,Amp,Apc,Arg,hArg,Cys,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A34是Asn,Aib,Gln,Ser,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A35是Asp,Aib,Glu,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A36是Trp,Acc,Aib,1Nal,2Nal,2-Pal,3-Pal,4-Pal,Phe,(X4,X5,X6,X7,X8)Phe,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A37是Lys,Amp,Apc,Arg,hArg,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A38是His,Amp,2-Pal,3-Pal,4-Pal,Phe,Tyr,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A39是Asn,Aib,Gln,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A40是Ile,Acc,Aib,Ser,Thr,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A41是Thr,Aib,Acc,Asn,Gln,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A42是Gln,Acc,Aib,Asn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A43是Acc,Ado,Aib,Ala,Asn,Asp,Cys,Gln,His,Phe,Thr,Trp,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
R1是OH,NH2,(C1-C30)烷氧基,或NH-X2-CH2-Z0,其中X2是(C0-C30)烃基,Z0是H,OH,CO2H,或CONH2;
R2,R3,R4和R5各独立选自H,(C1-C30)烷基,(C1-C30)杂烷基,(C1-C30)酰基,(C2-C30)烯基,(C2-C30)炔基,芳基(C1-C30)烷基,芳基(C1-C30)酰基,取代的(C1-C30)烷基,取代的(C1-C30)杂烷基,取代的(C1-C30)酰基,取代的(C2-C30)烯基,取代的(C2-C30)炔基,取代的芳基(C1-C30)烷基,和取代的芳基(C1-C30)酰基;假设R2是(C1-C30)酰基,芳基(C1-C30)酰基,取代的(C1-C30)酰基,或取代的芳基(C1-C30)酰基,则R3是H,(C1-C30)烷基,(C1-C30)杂烷基,(C2-C30)烯基,(C2-C30)炔基,芳基(C1-C30)烷基,取代的(C1-C30)烷基,取代的(C1-C30)杂烷基,取代的(C2-C30)烯基,取代的(C2-C30)炔基,或取代的芳基(C1-C30)烷基;进一步假设R4是(C1-C30)酰基,芳基(C1-C30)酰基,取代的(C1-C30)酰基,或取代的芳基(C1-C30)酰基,则R5是H,(C1-C30)烷基,(C1-C30)杂烷基,(C2-C30)烯基,(C2-C30)炔基,芳基(C1-C30)烷基,取代的(C1-C30)烷基,取代的(C1-C30)杂烷基,取代的(C2-C30)烯基,取代的(C2-C30)炔基,或取代的芳基(C1-C30)烷基;
n是每次出现独立(independently for each occurrence)的1至5(包括5)中的整数;
s,t,x和y分别是每次出现独立的1至30(包括30)中的整数;及
X4,X5,X6,X7和X8分别是每次出现独立的H,F,Cl,Br,I,(C1-10)烷基,取代的(C1-10)烷基,芳基,取代的芳基,OH,NH2,NO2,或CN。
上面通式(I)包含的化合物的子集(A)如下,其中:
A4是Gly;
A5是Thr;
A6是Phe;
A7是Ile或A6c;
A8是Ser;
A9是Asp;
A10是Tyr;
A11是Ser,A5c,或A6c;
A12是Ile;
A13是Ala或Aib;
A14是Met,A5c,A6c,或Nle;
A15是Asp;
A16是Lys;
A17是Ile;
A18是His;
A19是Gln;
A20是Gln;
A21是Asp;
A22是Phe;
A23是Val;
A24是Asn;
A25是Trp;
A26是Leu;
A27是Leu;
A28是Ala;
A29是Gln;
A30是Lys;
A31是Gly,His,Orn(N-C(O)-(CH2)12-CH3),或缺失;
A32是Lys,Cys,Cys(琥珀酰亚胺-N-(CH2)11-CH3),Cys(琥珀酰亚胺-N-(CH2)15-CH3),Orn(N-C(O)-(CH2)10-CH3),Orn(N-C(O)-(CH2)14-CH3),或缺失;
A33是Lys,Cys,Cys(琥珀酰亚胺-N-(CH2)11-CH3),Cys(琥珀酰亚胺-N-(CH2)15-CH3),Orn(N-C(O)-(CH2)10-CH3),或Orn(N-C(O)-(CH2)14-CH3),或缺失;
A34是Asn或缺失;
A35是Asp,Orn(N-C(O)-(CH2)12-CH3),或缺失;
A36是Trp或缺失;
A37是Lys或缺失;
A38是His或缺失;
A39是Asn或缺失;
A40是Ile,A5c,A6c,或缺失;
A41是Thr,A5c,A6c,或缺失;
A42是Gln,Cys(Psu),或缺失;
A43是Ado,Ala,Asn,Asp,Cys,Cys(琥珀酰亚胺-N-(CH2)11-CH3),Cys(琥珀酰亚胺-N-(CH2)15-CH3),His,Lys(N-C(O)-(CH2)10-CH3),Lys(N-C(O)-(CH2)14-CH3),Orn(N-C(O)-(CH2)14-CH3),Phe,Thr,Trp,或缺失;并
假设A7,A11,A13,A14,A31,A35,A40,A41和A42中至少1个不是天然GIP相应位置的氨基酸残基。
上面子集(A)的化合物的子集如下,其中:
A7是Ile;
A13是Ala或Aib;
A14是Met,A5c,A6c,或Nle;
A31是Gly;
A35是Asp;和
A42是Gln.
上面子集(A)的化合物的子集如下,其中:
A7是A6c;
A11是Ser;
A13是Ala;
A14是Met或Nle;
A31是Gly或Orn(N-C(O)-(CH2)12-CH3);
A32是Lys;
A33是Lys;
A35是Asp或Orn(N-C(O)-(CH2)12-CH3);
A40是Ile;
A41是Thr或A6c;
A42是Gln或Cys(Psu);和
A43是缺失。
通式(I)的优选化合物为:
实施例1:(A5c11,41)hGIP(1-42)-OH(SEQ ID NO:4);
实施例2:(A5c11,40)hGIP(1-42)-OH(SEQ ID NO:5);
实施例3:(A5c11,His43)hGIP(1-43)-OH(SEQ ID NO:6);
实施例4:(A5c11,Asn43)hGIP(1-43)-OH(SEQ ID NO:7);
实施例5:(Aib13,Asp43)hGIP(1-43)-NH2(SEQ ID NO:8);
实施例6:(Aib13,Nle14,A5c40)hGIP(1-42)-OH(SEQ ID NO:9);
实施例7:(Aib13,A5c40)hGIP(1-42)-OH(SEQ ID NO:10);
实施例8:(A5c11,Ala43)hGIP(1-43)-OH(SEQ ID NO:11);
实施例9:(Aib13,Nle14,Phe43)hGIP(1-43)-OH(SEQ ID NO:12);
实施例10:(A5c11,Thr43)hGIP(1-43)-OH(SEQ ID NO:13);
实施例11:(A6c11,14,41)hGIP(1-42)-OH(SEQ ID NO:14);
实施例12:(Aib13,Trp43)hGIP(1-43)-OH(SEQ ID NO:15);
实施例13:(A5c11,Ado43)hGIP(1-43)-OH(SEQ ID NO:16);
实施例14:(A6c11,14,40)hGIP(1-42)-OH(SEQ ID NO:17);
实施例15:[A6c7,Cys(Psu)42]hGIP(1-42)-OH(SEQ ID NO:18);
实施例16:(A6c7,41)hGIP(1-42)-OH(SEQ ID NO:19);
实施例17:(A6c7,41,Nle14)hGIP(1-42)-OH(SEQ ID NO:20);
实施例18:[A6c7,Orn35(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH(SEQ IDNO:21);
实施例19:[A6c7,Orn31(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH(SEQ IDNO:22);
实施例20:(A5c11,14,His43)hGIP(1-43)-OH(SEQ ID NO:23);
实施例21:(A5c11,Nle14,His43)hGIP(1-43)-OH(SEQ ID NO:24);
实施例22:[A5c11,Orn32(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQID NO:25);
实施例23:[A5c11,Orn33(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQID NO:26);
实施例24:[A5c11,Orn43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH(SEQ IDNO:27);
实施例25:[A5c11,Cys32(琥珀酰亚胺-N-(CH2)15-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:28);
实施例26:[A5c11,Cys33(琥珀酰亚胺-N-(CH2)15-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:29);
实施例27:[A5c11,Cys43(琥珀酰亚胺-N-(CH2)15-CH3)]hGIP(1-43)-OH(SEQ ID NO:30);
实施例28:(A5c11)hGIP(1-30)-NH2(SEQ ID NO:31);
实施例29:(A5c11,His31)hGIP(1-31)-NH2(SEQ ID NO:32);
实施例30:(A5c11,14)hGIP(1-30)-NH2(SEQ ID NO:33);
实施例31:(A5c11,41,Cys32)hGIP(1-42)-NH2(SEQ ID NO:34);
实施例32:(A5c11,41,Cys33)hGIP(1-42)-NH2(SEQ ID NO:35);
实施例33:(A5c11,41,Cys43)hGIP(1-43)-NH2(SEQ ID NO:36);
实施例34:[A5c11,Orn32(N-C(O)-(CH2)10-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:37);
实施例35:[A5c11,Orn33(N-C(O)-(CH2)10-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:38);
实施例36:[A5c11,Lys43(N-C(O)-(CH2)10-CH3)]hGIP(1-43)-OH(SEQID NO:39);
实施例37:[A5c11,Cys32(琥珀酰亚胺-N-(CH2)11-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:40);
实施例38:[A5c11,Cys33(琥珀酰亚胺-N-(CH2)11-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:41);
实施例39:[A5c11,Cys43(琥珀酰亚胺-N-(CH2)11-CH3)]hGIP(1-43)-OH(SEQ ID NO:42);
实施例40:[A5c11,Lys43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH(SEQID NO:43);
实施例41:[A5c11,Orn32(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:44);和
实施例42:[A5c11,Orn33(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ ID NO:45).
根据本发明的另一个方面,上面总结的和在随附的权利要求书中要求的根据本发明的化合物可另外包含共价连接的PEG基,其中所述PEG基通过Cys(马来酰亚胺),hCys(马来酰亚胺),或Pen(马来酰亚胺)接头共价连接至化合物以形成Cys(琥珀酰亚胺-N-PEG),hCys(琥珀酰亚胺-N-PEG),或Pen(琥珀酰亚胺-N-PEG),其中“琥珀酰亚胺-N-PEG”为下面定义的线性或分支的。所述PEG基具有从约2,000至约80,000的平均分子量,优选的所述PEG基选自5K PEG,10K PEG,20K PEG,30K PEG,40K PEG,50K PEG,和60K PEG以形成Cys(琥珀酰亚胺-N-5K PEG),Cys(琥珀酰亚胺-N-10KPEG),Cys(琥珀酰亚胺-N-20K PEG),Cys(琥珀酰亚胺-N-30K PEG),Cys(琥珀酰亚胺-N-40K PEG),Cys(琥珀酰亚胺-N-50K PEG),Cys(琥珀酰亚胺-N-60K PEG),hCys(琥珀酰亚胺-N-5K PEG),hCys(琥珀酰亚胺-N-10K PEG),hCys(琥珀酰亚胺-N-20K PEG),hCys(琥珀酰亚胺-N-30K PEG),hCys(琥珀酰亚胺-N-40K PEG),hCys(琥珀酰亚胺-N-50K PEG),hCys(琥珀酰亚胺-N-60K PEG),Pen(琥珀酰亚胺-N-5K PEG),Pen(琥珀酰亚胺-N-10K PEG),Pen(琥珀酰亚胺-N-20K PEG),Pen(琥珀酰亚胺-N-30K PEG),Pen(琥珀酰亚胺-N-40K PEG),Pen(琥珀酰亚胺-N-50K PEG),或Pen(琥珀酰亚胺-N-60K PEG)。
PEG化发生在16,30,和31-43位的任一氨基酸残基,优选的在32,33和43位的任一氨基酸残基,其中Cys(琥珀酰亚胺-N-PEG),hCys(琥珀酰亚胺-N-PEG),或Pen(琥珀酰亚胺-N-PEG)位于任一所述氨基酸残基位置。
此外,上面的通式(I)可扩展为在A44-A47位提供PEG化位点。本发明所述PEG化化合物的C端可进行酰胺化,例如,(A5c11,41)hGIP(1-42)-NH2(SEQ ID NO:68),或其可保留为游离酸,例如,(A5c11,41)hGIP(1-42)-OH(SEQID NO:4)。
所述PEG化化合物的优选化合物为:
实施例43:[A5c11,41,Cys32(琥珀酰亚胺-N-20KPEG)]hGIP(1-42)-NH2(SEQ ID NO:46);
实施例44:[A5c11,41,Cys33(琥珀酰亚胺-N-20KPEG)]hGIP(1-42)-NH2(SEQ ID NO:47);
实施例45:[A5c11,41,Cys43(琥珀酰亚胺-N-20KPEG)]hGIP(1-43)-NH2(SEQ ID NO:48);
实施例46:[A5c11,41,Cys43(琥珀酰亚胺-N-30KPEG)]hGIP(1-43)-NH2(SEQ ID NO:49);
实施例47:[A5c11,Nle14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:50);
实施例48:[A5c11,Nle14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:51);
实施例49:[A5c11,Nle14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:52);
实施例50:[A5c11,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-43)-NH2(SEQ ID NO:53);
实施例51:[A5c11,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:54);
实施例52:[A5c11,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:55);
实施例53:[A5c11,Nle14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20KPEG)]hGIP(1-43)-NH2(SEQ ID NO:56);
实施例54:[A5c11,Nle14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:57);
实施例55:[A5c11,Nle14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:58);
实施例56:[A5c11,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:59);
实施例57:[A5c11,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:60);
实施例58:[A5c11,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:61);
实施例59:[A5c11,14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-43)-NH2(SEQ ID NO:62);
实施例60:[A5c11,14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:63);
实施例61:[A5c11,14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:64);
实施例62:[A5c11,14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:65);
实施例63:[A5c11,14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:66);和
实施例64:[A5c11,14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:67).
附图简述
图1显示了实施例1-7的化合物和天然GIP对Sprague Dawley大鼠胰岛素释放的体内作用。
发明详述
本申请使用以下一般理解的缩写:
Abu:α-氨基丁酸
Acc:1-氨基-1-环(C3-C9)烷基羧酸
A3c:1-氨基-1-环丙烷羧酸
A4c:1-氨基-1-环丁烷羧酸
A5c:1-氨基-1-环戊烷羧酸
A6c:1-氨基-1-环己烷羧酸
Act:4-氨基-4-羧基四氢吡喃
Ado:12-氨基十二烷酸
Aib:α-氨基异丁酸
Aic:2-氨基茚-2-羧酸
Ala或A:丙氨酸
β-Ala:β-丙氨酸
Amp:4-氨基-苯基丙氨酸
Apc:4-氨基-4-羧基哌啶
Arg或R:精氨酸
hArg:高精氨酸
Asn或N:天冬酰胺
Asp或D:天冬氨酸
Aun:11-氨基十一酸
Ava:5-氨基戊酸
Cha:β-丙氨酸环己酯
Cys或C:半胱氨酸
Dhp:3,4-脱氢脯氨酸
Dmt:5,5-二甲基噻唑烷-4-羧酸
Gaba:γ-氨基丁酸
Gln或Q:谷氨酰胺
Glu或E:谷氨酸
Gly或G:甘氨酸
His或H:组氨酸
4Hppa:3-(4-羟苯基)丙酸
3Hyp:3-羟脯氨酸
4Hyp:4-羟脯氨酸
hPro:高脯氨酸
Ile或I:异亮氨酸
4Ktp:4-酮脯氨酸
Leu或L:亮氨酸
Lys或K:赖氨酸
Met或M:甲硫氨酸
Nle:正亮氨酸
Nme-Tyr:N-甲基-酪氨酸
1Nal或1-Nal:β-(1-萘基)丙氨酸
2Nal或2-Nal:β-(2-萘基)丙氨酸
Nle:正亮氨酸
Nva:正缬氨酸
Orn:鸟氨酸
2Pal或2-Pal:β-(2-吡啶)丙氨酸
3Pal或3-Pal:β-(3-吡啶)丙氨酸
4Pal或4-Pal:β-(4-吡啶)丙氨酸
Pen:青霉胺
Phe或F:苯丙氨酸
(3,4,5F)Phe:3,4,5-三氟苯丙氨酸
(2,3,4,5,6)Phe:2,3,4,5,6-五氟苯丙氨酸
Pro或P:脯氨酸
Psu:N-丙基琥珀酰亚胺
Ser或S:丝氨酸
Taz:β-(4-噻唑基)丙氨酸
3Thi:β-(3-噻吩基)丙氨酸
Thr或T:苏氨酸
Thz:硫代脯氨酸
Tic:四氢异喹啉-3-羧酸
Tle:叔亮氨酸
Trp或W:色氨酸
Tyr或Y:酪氨酸
Val或V:缬氨酸
此处使用的一些其他缩写定义如下:
Act:乙腈
Boc:叔丁氧羟基
BSA:牛血清白蛋白
DCM:二氯甲烷
DIPEA:二异丙基乙胺
DMF:二甲基甲酰胺
ESI:电喷射离子化
Fmoc:9-芴甲氧羰基
HBTU:苯并三唑-1-甲基脲六氟磷酸酯
(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexaf luorophosphate)
HOBT:1-羟基苯并三唑
HPLC:高效液相色谱
IBMX:异丁基甲基黄嘌呤
LC-MS:液相色谱-质谱
Mtt:甲基三苯甲基
NMP:N-甲基吡咯烷酮
5K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约5,000的平均总分子量
10K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约10,000的平均总分子量
20K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约20,000的平均总分子量
30K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约30,000的平均总分子量
40K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约40,000的平均总分子量
50K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约50,000的平均总分子量
60K PEG:聚乙二醇,其可能包括其他官能团或基例如接头,并且其为如下面定义的线性或分支的,具有约60,000的平均总分子量
tBu:叔丁基
TIS:三异丙基硅烷
Trt:三苯甲基
TFA:三氟乙酸
Z:苄氧羰基
“Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH 3)”的结构为:
其中,x=1-30,y=1-30。
“hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”的结构为:
其中,x=1-30,y=1-30。
“Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”的结构为:
其中,x=1-30,y=1-30。
“Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”的结构为:
其中,s=1-30,t=1-30。
“hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”的结构为:
其中,s=1-30,t=1-30。
“Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”的结构为:
其中,s=1-30,t=1-30。
“Pen(琥珀酰亚胺-N-PEG)”的结构为:
“Cys(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-PEG)”的结构为:
“Cys(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(PEG)-CH2-PEG)”的结构为:
除了N-端氨基酸以外,在此公开中的所有氨基酸缩写(例如,Ala)代表结构-NH-CI(R′)-CO-,其中R和R′分别独立的为氢或氨基酸侧链(例如R=CH3和R′=H表示Ala),或R和R′可连接形成环状体系。对N-端氨基酸,缩写代表结构(R2R3)N-CI(R′)-CO-,其中R2和R3在上面的通式(I)中定义。
术语“(C1-C30)烃基”包括烷基、烯基和炔基,在烯基和炔基的情况下为C2-C30。
本发明的肽在此处也通过另一种格式表示,例如(A5c2)hGIP(1-42)-OH(SEQ ID NO:3),与天然序列相比取代的氨基酸位于括号内(例如,在hGIP中A5c2取代Ala2)。圆括号内的数字指肽中的氨基酸数(例如,hGIP(1-42)-OH(SEQ ID NO:1)为hGIP肽序列的1至42位氨基酸)。在hGIP(1-30)-NH2(SEQ ID NO:2)中的名称“NH2”表示肽的C-端是酰胺化的;hGIP(1-42)(SEQ ID NO:1)或hGIP(1-42)-OH(SEQ ID NO:1)表示C-端是游离酸。
人GIP(“hGIP”)的氨基酸序列为:
Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His-Gln-Gln-Asp-Phe-Val-
1 5 10 15 20
Asn-Trp-Leu-Leu-Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln.(SEQ ID NO:1)
25 30 35 40
“酰基”指R″-C(O)-,其中R″为H,烷基,取代的烷基,杂烷基,取代的杂烷基,烯基,取代的烯基,芳基,烷基芳基,或取代的烷基芳基。
“烷基”指包含1个或多个碳原子的烃基,其中如果有多个碳原子,其通过单键连接。烷基烃基可为直链或包含1个或多个分支或环状基团。
“取代的烷基”指烷基,其中烃基的1个或多个氢原子被1个或多个取代基替换,所述取代基选自卤素,(即,氟、氯、溴和碘),-OH,-CN,-SH,-NH2,-NHCH3,-NO2,C1-20卤素取代的烷基,-CF3,-OCH3,-OCF3,和(CH2)0-20-COOH。在不同的实施方案中存在1、2、3或4个取代基。(CH2)0-20-COOH的存在导致烷基酸的产生。烷基酸的示例包括或包含(CH2)0-20-COOH(包括2-降莰烷乙酸)、叔丁酸和3-环戊基丙酸。
“杂烷基”指烷基,其中烃基的1个或多个氢原子被1个或多个以下基团替换:氨基(amino)、酰氨基(amido)、-O-,-S-或羰基。在不同的实施方案中存在1或2个杂原子。
“取代的杂烷基”指杂烷基,其中杂烷基的氢原子被1个或多个取代基替换,所述取代基选自卤素,-OH,-CN,-SH,-NH2,-NHCH3,-NO2,-C1-20卤素取代的烷基,-CF3,-OCH3,-OCF3,和(CH2)0-20-COOH。在不同的实施方案中存在1、2、3或4个取代基。
“烯基”指由2个或多个碳原子组成的烃基,其中存在1个或多个碳-碳双键。烯烃基可为直链或包含1个或多个分支或环状基团。
“取代的烯基”指烯基,其中1个或多个氢原子被1个或多个取代基替换,所述取代基选自卤素,OH,-CN,-SH,-NH2,-NHCH3,-NO2,-C1-20卤素取代的烷基,-CF3,-OCH3,-OCF3,和(CH2)0-20-COOH。在不同的实施方案中存在1、2、3或4个取代基。
“芳基”指任选取代的芳香基团,所述芳香基团含有至少一个具有共轭的π电子体系的环,包含达3个共轭的或融合的环体系。芳基包括碳环芳基、杂环芳基和联芳基。优选的,芳基为5或6元环。用于杂环芳基的优选原子为1或多个硫、氧和/或氮。芳基的示例包括苯基、1-萘基、2-萘基、吲哚、喹啉、1-咪唑和9-蒽。芳基取代基选自C1-20烷基,-C1-20烷氧基,卤素,-OH,-CN,-SH,-NH2,-NO2,-C1-20卤素取代的烷基,-CF3,-OCF3,和(CH2)0-20-COOH。在不同的实施方案中芳基包含0、1、2、3或4个取代基。
“烷基芳基”指连接至“芳基”的“烷基”。
合成
此发明的肽可通过标准固相肽合成制备。见,例如Stewart,J.M.,等人,1984,Solid Phase Synthesis,Pierce Chemical Co.,第二版。如果R1是NH-X2-CH2-CONH2,即Z0=CONH2,则肽合成从偶联至Rink酰胺MBHA树脂的Fmoc-HN-X2-CH2-CONH2开始。如果R1是NH-X2-CH2-COOH,即Z0=COOH,则肽合成从偶联至Wang树脂的Fmoc-HN-x2-CH2-COOH开始。在此特定步骤中,使用2摩尔当量的Fmoc-HN-X2-COOH,HBTU和HOBt以及10摩尔当量的DIPEA。偶联时间为约8小时。
在包含A5c,A6c,和/或Aib的本发明GIP类似物的合成中,用于这些残基和紧接其后的残基的偶联时间为2小时。
上面通式的取代基R2和R3可通过本领域已知的标准方法连接至N-端氨基酸A1的游离胺。例如,烷基,例如(C1-C30)烷基,可使用还原烷基化连接。羟烷基,例如(C1-C30)羟烷基,也可使用还原烷基化连接,其中用叔丁基酯保护游离羟基。酰基,例如-C(O)X3,可通过游离酸例如-X3COOH的偶联连接至N-端氨基酸的游离胺,通过在二氯甲烷中将完整树脂和各3摩尔当量的游离酸和二异丙基碳二亚胺混合约1小时(进行此偶联)。如果游离酸包含游离羟基,例如3-氟-4-羟基苯乙酸,则应另外加入3摩尔当量HOBT进行偶联。
以下实施例描述了制备本发明肽的合成方法,所述方法是本领域技术人员所熟知的。其他方法也是本领域技术人员所公知的。提供的实施例是为了说明的目的,而无意以任何方式限制本发明的范围。
实施例15:[A6c
7
,Cys(Psu)
42
]hGIP(1-42)-OH
使用微波辅助的Fmoc化学在Liberty肽合成仪(CEM;Matthews,NC,USA)上以0.1mmole规模进行固相肽合成以组装肽。使用预上样的Fmoc-Cys(Trt)-Wang树脂(0.59mmole/g;Novabiochem,San Diego,CA,USA)生成C端酸肽。树脂(0.17g)与15ml二甲基甲酰胺(DMF)一起置于50ml圆锥管并上样至合成仪上的树脂位置。之后通过自动过程将树脂定量转移至反应容器。使用用于0.1mmole规模合成的标准Liberty合成方案。此方案包括通过用7ml 20%哌啶(含有0.1M溶于DMF的1-羟基苯并三唑(HOBT))的初始处理去保护N-端Fmoc基。初始的去保护步骤使用微波功率(45瓦特,最高温度75℃)和氮气鼓泡(3秒开/7秒关)进行30秒。之后排空反应容器,进行第二次哌啶处理,除了持续3分钟以外与第一次处理相同。之后排空树脂并用DMF彻底清洗几次。之后加入保护氨基酸Fmoc-Thr(tBu)-OH(预先配制为0.2M溶于DMF的储液)(2.5ml,5当量),接着加入1.0ml 0.45M(4.5当量)溶于DMF的HBTU[苯并三唑-1-四甲基脲六氟磷酸酯]。之后加入0.5ml 2M(10当量)溶于NMP(N-甲基吡咯烷酮)的DIPEA(二异丙基乙胺)。使用20瓦特微波功率在最高温度75℃下和相同速率的氮气鼓泡进行5分钟偶联步骤。
在初始的偶联步骤之后排空反应容器并重复偶联一次。之后起始与循环1类似的循环2。类似的引入所有氨基酸,并在全序列中应用双偶联策略。循环1-3,19-20,25-26,和30-39包含紧接在偶联步骤后的加帽程序。通过加入7mL 0.5M乙酸酐(含有0.015M溶于NMP的HOBT)和2mL 2MDIPEA溶液进行加帽,使用多步骤微波方案:50瓦特功率30秒(65℃最高温度),之后30秒微波关闭,之后第二轮30秒微波打开(50瓦特),和之后再次无微波功率30秒。之后排空树脂,用DMF彻底清洗。使用以下氨基酸(Advanced Chemtech,Louisville,KY,USA):循环1:Fmoc-Thr(OtBu)-OH;循环2:Fmoc-Ile-OH;循环3:Fmoc-Asn(Trt)-OH;循环4:Fmoc-His(Trt)-OH;循环5:Fmoc-Lys(Boc)-OH;循环6:Fmoc-Trp(Boc)-OH;循环7:Fmoc-Asp(OtBu)-OH;循环8:Fmoc-Asn(Trt)-OH;循环9:Fmoc-Lys(Boc)-OH;循环10:Fmoc-Lys(Boc)-OH;循环11:Fmoc-Gly-OH;循环12:Fmoc-Lys(Boc)-OH;循环13:Fmoc-Gln(Trt)-OH;循环14:Fmoc-Ala-OH;循环15:Fmoc-Leu-OH;循环16:Fmoc-Leu-OH;循环17:Fmoc-Trp(Boc)-OH;循环18:Fmoc-Asn(Trt)-OH;循环19:Fmoc-Val-OH;循环20:Fmoc-Phe-OH;循环21:Fmoc-Asp(OtBu)-OH;循环22:Fmoc-Gln(Trt)-OH;循环23:Fmoc-Gln(Trt)-OH;循环24:Fmoc-His(Trt)-OH;循环25:Fmoc-Ile-OH;循环26:Fmoc-Lys(Boc)-OH;循环27:Fmoc-Asp(OtBu)-OH;循环28:Fmoc-Met-OH;循环29:Fmoc-Ala-OH;循环30:Fmoc-Ile-OH;循环31:Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH;循环32:Fmoc-Asp(OtBu)-OH;循环33:Fmoc-Ser(tBu)-OH;循环34:Fmoc-A6c-OH.循环35:Fmoc-Phe-OH;循环36:Fmoc-Gly-Thr(psiMe,Me,Pro)-OH;循环37:Fmoc-Glu(OtBu)-OH;循环38:Fmoc-Ala-OH;和循环39:Fmoc-Tyr(tBu)-OH。Fmoc-His(Trt)-OH的偶联方案是标准方案的略微修饰版本。在开始2分钟关闭微波率,之后4分钟打开微波(20瓦特;最高温度50℃)。在肽骨架组装结束后,用标准哌啶处理去除N-端的Fmoc基团。之后用DMF彻底清洗树脂,并转移回50ml圆锥管,使用DMF作为转移溶液。
去保护树脂,用5ml以下试剂处理切割树脂:5%TIS,2%水,5%(w/v)二硫苏糖醇(DTT),88%TFA,混合3.5小时。滤出液收集在45ml冷无水乙醚中。在冷离心机中以3500RPM离心沉淀10分钟。倾倒出乙醚,将肽重悬于新鲜的乙醚。乙醚处理共进行2次。最后1次乙醚清洗后,将肽在空气中干燥以去除残留乙醚。肽沉淀用8ml乙腈(Acn)和之后用8ml去离子水重悬,使其充分溶解。之后用质谱分析肽溶液。应用电喷射离子化的质谱鉴定出质量为4970.7道尔顿的主要产物;对应线性产物。用HPLC分析粗产物(约500mg),使用250x4.6毫米C18柱(Phenomenex;Torrance,CA,USA)和2-80%乙腈(0.1%TFA)梯度进行30分钟。之后用N-丙基马来酰亚胺(Pma)衍生粗产物以生成半胱氨酸侧链上的丙基琥珀酰亚胺(Psu)衍生物。将粗制线性肽以5mg/ml溶于水,用碳酸铵调节为pH6.5。加入5当量Pma并持续搅拌30秒。使用5当量二硫苏糖醇(DTT)淬灭过量的Pma。通过质谱分析衍生的肽溶液。质量分析鉴定出质量为5109.7道尔顿的主要产物;对应期望的Psu衍生产物。之后通过制备型HPLC纯化产物,使用与之前类似的梯度。通过HPLC(用于分析纯度,为96.60%)和质谱(5108.9道尔顿)分析纯化产物,之后冻干。冻干后,得到10.3mg纯化产物,相当于2%的产率。
实施例18:[A6c
7
,Orn
35
(N-C(O)-(CH
2
)
12
-CH
3
)]hGIP(1-42)-OH
使用微波辅助的Fmoc化学在Liberty肽合成仪(CEM;Matthews,NC,USA)上以0.1mmole规模进行固相肽合成以组装肽。使用预上样的Fmoc-Cys(Trt)-Wang树脂(0.59mmole/g;Novabiochem,San Diego,CA,USA)生成C端酸肽。树脂(0.17g)与15ml二甲基甲酰胺(DMF)一起置于50ml圆锥管并上样至合成仪上的树脂位置。之后通过自动过程将树脂定量转移至反应容器。使用用于0.1mmole规模合成的标准liberty合成方案。此方案包括通过用7ml 20%哌啶(含有0.1M溶于DMF的1-羟基苯并三唑(HOBT))的初始处理去保护N-端Fmoc基。初始的去保护步骤使用微波功率(45瓦特,最高温度75℃)和氮气鼓泡(3秒开/7秒关)进行30秒。之后排空反应容器,进行第二次哌啶处理,除了持续3分钟以外与第一次处理相同。之后排空树脂并用DMF彻底清洗几次。之后加入保护氨基酸Fmoc-Thr(tBu)-OH(预先配制为0.2M溶于DMF的储液)(2.5ml,5当量),接着加入1.0ml 0.45M(4.5当量)溶于DMF的HBTU[苯并三唑-1-四甲基脲六氟磷酸酯]。之后加入0.5ml 2M(10当量)溶于NMP(N-甲基吡咯烷酮)的DIPEA(二异丙基乙胺)。使用20瓦特微波功率在最高温度75℃下和相同速率的氮气鼓泡进行5分钟偶联步骤。
在初始的偶联步骤之后排空反应容器并重复偶联一次。之后起始与循环1类似的循环2。类似的引入所有氨基酸,并在全序列中应用双偶联策略。循环1-3,19-20,25-26,和30-39包含紧接在偶联步骤后的加帽程序。通过加入7mL 0.5M乙酸酐(含有0.015M溶于NMP的HOBT)和2mL 2MDIPEA溶液进行加帽,使用多步骤微波方案:50瓦特功率30秒(65℃最高温度),之后30秒微波关闭,之后第二轮30秒微波功率打开(50瓦特),和之后再次无微波功率30秒。之后排空树脂,用DMF彻底清洗。使用以下氨基酸(Advanced Chemtech,Louisville,KY,USA):循环1:Fmoc-Thr(tBu)-OH;循环2:Fmoc-Ile-OH;循环3:Fmoc-Asn(Trt)-OH;循环4:Fmoc-His(Trt)-OH;循环5:Fmoc-Lys(Boc)-OH;循环6:Fmoc-Trp(Boc)-OH;循环7:Fmoc-Orn(Mtt)-OH;循环8:Fmoc-Asn(Trt)-OH;循环9:Fmoc-Lys(Boc)-OH;循环10:Fmoc-Lys(Boc)-OH;循环11:Fmoc-Gly-OH;循环12:Fmoc-Lys(Boc)-OH;循环13:Fmoc-Gln(Trt)-OH;循环14:Fmoc-Ala-OH;循环15:Fmoc-Leu-OH;循环16:Fmoc-Leu-OH;循环17:Fmoc-Trp(Boc)-OH;循环18:Fmoc-Asn(Trt)-OH;循环19:Fmoc-Val-OH;循环20:Fmoc-Phe-OH;循环21:Fmoc-Asp(OtBu)-OH;循环22:Fmoc-Gln(Trt)-OH;循环23:Fmoc-Gln(Trt)-OH;循环24:Fmoc-His(Trt)-OH;循环25:Fmoc-Ile-OH;循环26:Fmoc-Lys(Boc)-OH;循环27:Fmoc-Asp(OtBu)-OH;循环28:Fmoc-Met-OH;循环29:Fmoc-Ala-OH;循环30:Fmoc-Ile-OH;循环31:Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH;循环32:Fmoc-Asp(OtBu)-OH;循环33:Fmoc-Ser(tBu)-OH;循环34:Fmoc-A6c-OH;循环35:Fmoc-Phe-OH;循环36:Fmoc-Gly-Thr(psiMe,Me,Pro)-OH;循环37:Fmoc-Glu(OtBu)-OH;循环38:Fmoc-Ala-OH;和循环39:Boc-Tyr(tBu)-OH。Fmoc-His(Trt)-OH的偶联方案是标准方案的略微修饰版本。在开始2分钟关闭微波功率,之后4分钟打开微波功率(20瓦特;最高温度50℃)。
肽骨架完成后,用12ml溶于二氯甲烷(DCM)的1%三氟乙酸(TFA)/5%三异丙基硅烷(TIS)处理5分钟,N2鼓泡速率为5秒开,10秒关。之后排空树脂,再次用溶于DCM溶液的1%TFA/5%TIS处理5分钟。此步骤总共进行7次以有效去除鸟氨酸侧链上的Mtt基。树脂用DCM彻底清洗几次,之后用标准哌啶步骤处理以中和鸟氨酸δN上的残留TFA盐。使用标准氨基酸偶联方案将肉豆蔻酸(CH3-(CH2)12-COOH;Aldrich,St.Louis,MO,USA)(预先配制为溶于DMF中的0.2M溶液)偶联至鸟氨酸侧链。之后用DMF彻底清洗树脂并转移回50ml圆锥管,使用DMF作为转移溶剂。
去保护树脂,用5ml以下试剂处理切割树脂:5%TIS,2%水,5%(w/v)二硫苏糖醇(DTT),88%TFA,混合3.5小时。滤出液收集在45ml冷无水乙醚中。在冷离心机中以3500RPM离心沉淀10分钟。倾倒出乙醚,将肽重悬于新鲜的乙醚。乙醚处理共进行2次。最后1次乙醚清洗后,将肽在空气中干燥以去除残留乙醚。肽沉淀用8ml乙腈(Acn)和之后用8ml去离子水重悬,使其充分溶解。之后用质谱分析肽溶液。应用电喷射离子化的质谱鉴定出质量为5205.1道尔顿的主要产物;对应期望的线性产物。用HPLC分析粗产物(约500mg),使用250x4.6毫米C18柱(Phenomenex;Torrance,CA,USA)和2-80%乙腈(0.1%TFA)梯度进行30分钟。分析型HPLC鉴定出50%纯度的产物。之后用装备C18柱的制备型HPLC纯化肽,使用类似的洗脱梯度。纯化产物用HPLC(用于分析纯度,为97.40%)和质谱(5204.6道尔顿)再次分析,之后冻干。冻干后,得到6.2mg的纯化产物,相当于1.2%的产率。
此处公开的PEG化GIP化合物可基本上根据描述的实施例15化合物的合成方案合成,通过使用PEG-马来酰亚胺替代实施例15中使用的N-丙基马来酰亚胺作为起始原料。
本发明的其他肽可由本领域普通技术人员使用与在上面实施例中公开的类似合成方案制备。此处示例的化合物的物理数据见表1。
表1
功能试验
A.体外的hGIP受体结合试验
如下制备用于体外受体结合试验的膜:使用Brinkman Polytron(设置6,15秒)在冰冷的50mM Tris-HCl中匀浆表达人重组GIP受体的CHO-K1克隆细胞,之后以39,000g10分钟离心2次,2次离心中间用新鲜的缓冲液重悬。用于试验,在50mM Tris-HCl,0.1mg/ml杆菌肽和0.1%BSA中与0.05nM[125I]GIP(~2200Ci/mmol)一起孵育等分试样的清洗后的膜制剂,25℃下100分钟。最终的试验体积为0.5ml。使用Brandel多头过滤器快速滤过GF/C滤膜(在0.5%聚氮丙啶中预浸泡)终止孵育。之后用5-ml等分试样的冰冷缓冲液清洗各试管和滤膜3次。特异结合定义为结合的总放射性配体减去在1000nM GIP存在下结合的放射性配体。此处示例的化合物的体外hGIP受体结合数据见表2。
B.人和大鼠血浆半衰期试验
将GIP肽(50μl 1mg/ml)加入450μl血浆(人或大鼠),短暂涡旋并在37℃孵育。在不同时间例如在0,1,2,3,4,8,24,32,48,56,72小时取出50μl,与5μl甲酸和150μL乙腈在微离心管中混合,涡旋,并以10K rpm离心10分钟。将上清转移至注射小瓶并用LC-MS分析。LC-MS系统由具有ESI探针的API4000质谱仪组成。使用阳离子模式和全扫描检测。HPLC分离在Luna 3μC8(2),2x30毫米柱上进行,使用90%A至90%B梯度以0.3ml/分钟流速进行10分钟。缓冲液A是1%溶于水的甲酸,缓冲液B是1%溶于乙腈的甲酸。此处示例的化合物的人和大鼠血浆半衰期数据见表2。
表2
C.环AMP刺激的测定
1x105表达人重组GIP受体的CHO-K1或RIN-5F胰岛瘤细胞接种至24-孔培养板(Corning Incorporate,Corning,NY,USA)中培养过夜。用于试验,细胞与0.55mM调节至pH7.3的IBMX(Sigma,St.Louis,MO,USA)在500μl Hanks平衡盐溶液(Sigma,St.Louis,MO,USA)中预孵育10分钟。之后以100nM浓度加入GIP或其类似物。在37℃孵育30分钟后,将板置于冰上,加入500μl冰冷的无水乙醇终止反应。收集孔内含物,以2,700g在4℃离心20分钟以去除细胞碎片。上清中的cAMP水平通过放射性免疫分析(New England Nuclear,Boston,MA,USA)测定。
D.正常大鼠体内胰岛素分泌的测定
使用体重约275-300g的雄性Sprague Dawley大鼠作为实验对象。处理前1天,在水合氯醛(chlorohydrate)作用下经颈静脉植入右心房套管。每个套管用100u/ml肝素盐水填充并束紧。在给药化合物或载体(盐水/0.25%BSA)前,禁食大鼠约18小时。试验当天,解冻等分试样的化合物,使达到室温并充分涡旋。仔细检查是否有未溶解的化合物。在注射化合物/葡萄糖前10分钟,取出500μl血样品并用等体积的肝素化盐水(10u/ml)替换。在时间0时从套管中取出500μl血样品。接下来,将载体或合适剂量的化合物注射进套管,并用葡萄糖(1g/kg)或载体溶液推进去。最后,使用500μl体积的肝素化盐水(10u/ml)将剩余的葡萄糖推进套管。在葡萄糖给药后2.5,5,10,和20分钟取出额外500μl血样品;每次之后立即团注,通过套管静脉注射500μl肝素化盐水(10u/ml)。通过离心从血样品中收集血浆,并贮存于-20℃直至进行胰岛素含量测定。
图1显示了实施例1-7的化合物和天然GIP对Sprague Dawley大鼠胰岛素释放的体内作用。在表3中总结了图1中显示的总胰岛素分泌数值。
表3
在如上述相同的实验条件下单独检测了实施例20的化合物的体内作用,在表4中总结了实施例20的化合物的总胰岛素分泌数值。
表4
施用
本发明的肽可以可药用盐的形式提供。所述盐的示例包括但不局限于与下述酸形成的盐:有机酸(例如醋酸,乳酸,马来酸,柠檬酸,苹果酸,抗坏血酸,琥珀酸,苯甲酸,甲磺酸,甲苯磺酸,或双羟萘酸),无机酸(例如盐酸、硫酸或磷酸)和聚合酸(例如单宁酸,羧甲基纤维素,聚乳酸,聚乙醇酸,或聚乳酸-乙醇酸的共聚物)。产生本发明肽盐的一般方法是本领域所熟知的并可通过盐交换标准方法获得。由此,可将本发明肽的TFA盐(所述TFA盐来自肽纯化,通过制备型HPLC,使用含有TFA的缓冲溶液洗脱)转化为另一种盐,例如通过在小量0.25N乙酸水溶液中溶解所述肽得到乙酸盐。将得到的溶液应用于半制备(semi-prep)HPLC柱(Zorbax,300SB,C-8)。按下述洗脱柱:(1)0.1N醋酸铵水溶液,0.5小时,(2)0.25N醋酸水溶液,0.5小时,和(3)以4ml/分钟流速的线性梯度(20%至100%溶液B洗脱30分钟)(溶液A为0.25N醋酸水溶液;溶液B为0.25N溶于80∶20乙腈/水的醋酸)。收集含有肽的组分并冻干。
在此本发明组合物中的活性成分剂量可以变化;然而,活性成分的量必须能够获得合适的剂型。选择的剂量取决于期望的治疗效果、施用途径和治疗的持续时间。一般来说,用于此发明活性的有效剂量为1x10-7至200mg/kg/天,优选的1x10-4至100mg/kg/天范围内,其可作为单独剂量或分为多次剂量施用。
此发明的化合物可通过口服、肠胃外(例如肌肉、腹腔、静脉或皮下注射,或植入)、鼻、阴道、直肠、舌下或局部施用途径施用,并可与可药用载体配制以提供适用于各施用途径的剂型。
用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉末和颗粒。在这些固体剂型中,活性化合物与至少1种惰性可药用载体例如蔗糖、乳糖或淀粉混合。按照通常做法,这些剂型还可包含除了这些惰性稀释剂以外的其他物质,例如润滑剂例如硬脂酸镁。在胶囊、片剂和丸剂的情况下,剂型还可包含缓冲剂。片剂和丸剂的制备还可包含肠溶衣。
用于口服施用的液体剂型包括但不局限于可药用的乳剂、溶液、悬浮液、糖浆、酏剂等等,其包含本领域常用的惰性稀释剂例如水。除了这些惰性稀释剂,组合物还可包括佐剂,例如湿润剂,乳化和悬浮剂,和甜味剂,调味剂和香料。
根据此发明的用于肠胃外施用的制剂包括但不局限于无菌水性或非水性溶液、悬液、乳剂等等。非水性溶剂或载体的示例包括丙二醇、聚乙二醇、植物油例如橄榄油和玉米油、明胶和可注射的有机酯例如油酸乙酯。这些剂型还可包含佐剂,例如防腐剂、湿润剂、乳化剂和分散剂。它们可通过如下方式灭菌,例如用截留细菌的滤器过滤,在组合物中加入灭菌剂,照射组合物或加热组合物。它们还可被制造为无菌固体组合物的形式,其可在使用前立即溶于无菌水或一些其他无菌可注射介质。
用于直肠或阴道施用的组合物优选的为栓剂,其可包含除了活性物质以外的赋形剂例如可可油或栓剂蜡。
用于鼻或舌下施用的组合物的制备还可包含本领域熟知的标准赋形剂。
此外,此发明的化合物可在持续释放的组合物中施用,例如在以下专利和专利申请中所描述的。美国专利号5,672,659教授了包含生物活性剂和聚酯的持续释放组合物。美国专利号5,595,760教授了包含胶状形式生物活性剂的持续释放组合物。美国专利号5,821,221教授了包含生物活性剂和壳聚糖的聚合持续释放组合物。美国专利号5,916,883教授了包含生物活性剂和环糊精的持续释放组合物。PCT公开号WO99/38536教授了包含生物活性剂的可吸收持续释放组合物。PCT公开号WO00/04916教授了用水包油方法制备包含治疗剂例如肽的微颗粒的方法。PCT公开号WO00/09166教授了包含治疗剂例如肽和磷酸聚合物的复合物。PCT公开号WO00/25826教授了包含治疗剂例如肽和具有非聚合内酯的聚合物的复合物。
除非另外定义,此处使用的所有技术和科学术语与此发明所属领域普通技术人员通常理解的意思相同。此外,所有此处提及的出版物、专利申请、专利和其他参考资料在此以其整体引入作为参考。
Claims (35)
1.通式(I)的化合物,
(R2R3)-Tyr-Ala-Glu-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-A42-A43-R1,
(I)
其中:
A4是Gly,Acc,Aib,或β-Ala;
A5是Thr,Acc,Aib,或Ser;
A6是Phe,Acc,Aib,Aic,Cha,1Nal,2Nal,2-Pal,3-Pal,4-Pal,(X4,X5,X6,X7,X8)Phe或Trp;
A7是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val;
A8是Ser,Aib,或Thr;
A9是Asp,Aib,或Glu;
A10是Tyr,Acc,Cha,1Nal,2Nal,2-Pal,3-Pal,4-Pal,Phe,或(X4,X5,X6,X7,X8)Phe;
A11是Ser,Acc,Aib,Nle或Thr;
A12是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val;
A13是Ala,Acc,Aib,β-Ala,D-Ala,Gly,或Ser;
A14是Met,Abu,Acc,Aib,Ala,Cha,Ile,Leu,Nle,Phe,Tle,或Val;
A15是Asp,Aib,或Glu;
A16是Lys,Amp,Apc,Arg,hArg,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3);
A17是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val;
A18是His,Amp,Arg,2-Pal,3-Pal,或4-Pal,Phe,或Tyr;
A19是Gln,Aib,或Asn;
A20是Gln,Aib,或Asn;
A21是Asp,Aib,或Glu;
A22是Phe,Acc,Aib,AiC,Cha,1Nal,2Nal,2-Pal,3-Pal,4-Pal,(X4,X5,X6,X7,X8)Phe,或Trp;
A23是Val,Abu,Acc,Aib,Ala,Cha,Ile,Leu,Nle,或Tle;
A24是Asn,Aib,或Gln;
A25是Trp,Acc,Aib,1Nal,2Nal,2-Pal,3-Pal,4-Pal,Phe,或(X4,X5,X6,X7,X8)Phe;
A26是Leu,Acc,Aib,Cha,Ile,Nle,Phe,(X4,X5,X6,X7,X8)Phe或Tle;
A27是Leu,Acc,Aib,Cha,Ile,Nle,Phe,(X4,X5,X6,X7,X8)Phe或Tle;
A28是Ala,Aib,或Acc;
A29是Gln,Aib,Asn,或缺失;
A30是Lys,Amp,Apc,Arg,hArg,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A31是Gly,Acc,Aib,β-Ala,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),His,Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A32是Lys,Amp,Apc,Arg,hArg,Cys,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A33是Lys,Amp,Apc,Arg,hArg,Cys,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A34是Asn,Aib,Gln,Ser,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A35是Asp,Aib,Glu,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A36是Trp,Acc,Aib,1Nal,2Nal,2-Pal,3-Pal,4-Pal,Phe,(X4,X5,X6,X7,X8)Phe,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A37是Lys,Amp,Apc,Arg,hArg,Orn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A38是His,Amp,2-Pal,3-Pal,4-Pal,Phe,Tyr,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A39是Asn,Aib,Gln,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A40是Ile,Acc,Aib,Ser,Thr,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A41是Thr,Aib,Acc,Asn,Gln,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A42是Gln,Acc,Aib,Asn,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
A43是Acc,Ado,Aib,Ala,Asn,Asp,Cys,Gln,His,Gln,Phe,Thr,Trp,HN-CH((CH2)n-N(R4R5))-C(O),Cys(琥珀酰亚胺-N-烷基),hCys(琥珀酰亚胺-N-烷基),Pen(琥珀酰亚胺-N-烷基),Cys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3),Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3),或缺失;
R1是OH,NH2,(C1-C30)烷氧基,或NH-X2-CH2-Z0,其中X2是(C0-C30)烃基,Z0是H,OH,CO2H,或CONH2;
R2,R3,R4和R5各独立选自H,(C1-C30)烷基,(C1-C30)杂烷基,(C1-C30)酰基,(C2-C30)烯基,(C2-C30)炔基,芳基(C1-C30)烷基,芳基(C1-C30)酰基,取代的(C1-C30)烷基,取代的(C1-C30)杂烷基,取代的(C1-C30)酰基,取代的(C2-C30)烯基,取代的(C2-C30)炔基,取代的芳基(C1-C30)烷基,和取代的芳基(C1-C30)酰基;假设R2是(C1-C30)酰基,芳基(C1-C30)酰基,取代的(C1-C30)酰基,或取代的芳基(C1-C30)酰基,则R3是H,(C1-C30)烷基,(C1-C30)杂烷基,(C2-C30)烯基,(C2-C30)炔基,芳基(C1-C30)烷基,取代的(C1-C30)烷基,取代的(C1-C30)杂烷基,取代的(C2-C30)烯基,取代的(C2-C30)炔基,或取代的芳基(C1-C30)烷基;进一步假设R4是(C1-C30)酰基,芳基(C1-C30)酰基,取代的(C1-C30)酰基,或取代的芳基(C1-C30)酰基,则R5是H,(C1-C30)烷基,(C1-C30)杂烷基,(C2-C30)烯基,(C0-C30)炔基,芳基(C1-C30)烷基,取代的(C1-C30)烷基,取代的(C1-C30)杂烷基,取代的(C2-C30)烯基,取代的(C2-C30)炔基,或取代的芳基(C1-C30)烷基;
n是各自独立的1至5含端点的整数;
s,t,x和y分别是各自独立的1至30含端点的整数;及
X4,X5,X6,X7和X8分别是各自独立的H,F,Cl,Br,I,(C1-10)烷基,取代的(C1-10)烷基,芳基,取代的芳基,OH,NH2,NO2,或CN。
2.根据权利要求1的化合物或其可药用盐,其中:
A4是Gly;
A5是Thr;
A6是Phe;
A7是Ile或A6c;
A8是Ser;
A9是Asp;
A10是Tyr;
A11是Ser,A5c,或A6c;
A12是Ile;
A13是Ala或Aib;
A14是Met,A5c,A6c,或Nle;
A15是Asp;
A16是Lys;
A17是Ile;
A18是His;
A19是Gln;
A20是Gln;
A21是Asp;
A22是Phe;
A23是Val;
A24是Asn;
A25是Trp;
A26是Leu;
A27是Leu;
A28是Ala;
A29是Gln;
A30是Lys;
A31是Gly,His,Orn(N-C(O)-(CH2)12-CH3),或缺失;
A32是Lys,Cys,Cys(琥珀酰亚胺-N-(CH2)11-CH3),Cys(琥珀酰亚胺-N-(CH2)15-CH3),Orn(N-C(O)-(CH2)10-CH3),Orn(N-C(O)-(CH2)14-CH3),或缺失;
A33是Lys,Cys,Cys(琥珀酰亚胺-N-(CH2)11-CH3),Cys(琥珀酰亚胺-N-(CH2)15-CH3),Orn(N-C(O)-(CH2)10-CH3),或Orn(N-C(O)-(CH2)14-CH3),或缺失;
A34是Asn或缺失;
A35是Asp,Orn(N-C(O)-(CH2)12-CH3),或缺失;
A36是Trp或缺失;
A37是Lys或缺失;
A38是His或缺失;
A39是Asn或缺失;
A40是Ile,A5c,A6c,或缺失;
A41是Thr,A5c,A6c,或缺失;
A42是Gln,Cys(Psu),或缺失;
A43是Ado,Ala,Asn,Asp,Cys,Cys(琥珀酰亚胺-N-(CH2)11-CH3),Cys(琥珀酰亚胺-N-(CH2)15-CH3),His,Lys(N-C(O)-(CH2)10-CH3),Lys(N-C(O)-(CH2)14-CH3),Orn(N-C(O)-(CH2)14-CH3),Phe,Thr,Trp,或缺失;并
假设A7,A11,A13,A14,A31,A35,A40,A41和A42中至少1个不是天然GIP相应位置的氨基酸残基。
3.根据权利要求2的化合物或其可药用盐,其中所述化合物为:
(A5c11,41)hGIP(1-42)-OH(SEQ ID NO:4);
(A5c11,40)hGIP(1-42)-OH(SEQ ID NO:5);
(A5c11,His43)hGIP(1-43)-OH(SEQ ID NO:6);
(A5c11,Asn43)hGIP(1-43)-OH(SEQ ID NO:7);
(Aib11,Asp43)hGIP(1-43)-NH2(SEQ ID NO:8);
(Aib11,Nle14,A5c40)hGIP(1-42)-OH(SEQ ID NO:9);
(Aib11,A5c40)hGIP(1-42)-OH(SEQ ID NO:10);
(A5c11,Ala43)hGIP(1-43)-OH(SEQ ID NO:11);
(Aib13,Nle14,Phe43)hGIP(1-43)-OH(SEQ ID NO:12);
(A5c11,Thr43)hGIP(1-43)-OH(SEQ ID NO:13);
(A6c11,14,41)hGIP(1-42)-OH(SEQ ID NO:14);
(Aib13,Trp43)hGIP(1-43)-OH(SEQ ID NO:15);
(A5c11,Ado43)hGIP(1-43)-OH(SEQ ID NO:16);
(A6c11,14,40)hGIP(1-42)-OH(SEQ ID NO:17);
[A6c7,Cys(Psu)42]hGIP(1-42)-OH(SEQ ID NO:18);
(A6c7,41)hGIP(1-42)-OH(SEQ ID NO:19);
(A6c7,41,Nle14)hGIP(1-42)-OH(SEQ ID NO:20);
[A6c7,Orn35(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH(SEQ ID NO:21);
[A6c7,Orn31(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH(SEQ ID NO:22);
(A5c11,14,His43)hGIP(1-43)-OH (SEQ ID NO:23);
(A5c11,Nle14,His43)hGIP(1-43)-OH (SEQ ID NO:24);
[A5c11,Orn32(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:25);
[A5c11,Orn33(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:26);
[A5c11,Orn43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH(SEQ ID NO:27);
[A5c11,Cys32(琥珀酰亚胺-N-(CH2)15-CH3),His43]hGIP(1-43)-OH(SEQID NO:28);
[A5c11,Cys33(琥珀酰亚胺-N-(CH2)15-CH3),His43]hGIP(1-43)-OH(SEQID NO:29);
[A5c11,Cys43(琥珀酰亚胺-N-(CH2)15-CH3)]hGIP(1-43)-OH(SEQ IDNO:30);
(A5c11)hGIP(1-30)-NH2(SEQ ID NO:31);
(A5c11,His31)hGIP(1-31)-NH2(SEQ ID NO:32);
(A5c11,14)hGIP(1-30)-NH2(SEQ ID NO:33);
(A5c11,41,Cys32)hGIP(1-42)-NH2(SEQ ID NO:34);
(A5c11,41,Cys33)hGIP(1-42)-NH2(SEQ ID NO:35);
(A5c11,41,Cys43)hGIP(1-43)-NH2(SEQ ID NO:36);
[A5c11,Orn32(N-C(O)-(CH2)10-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:37);
[A5c11,Orn33(N-C(O)-(CH2)10-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:38);
[A5c11,Lys43(N-C(O)-(CH2)10-CH3)]hGIP(1-43)-OH(SEQ ID NO:39);
[A5c11,Cys32(琥珀酰亚胺-N-(CH2)11-CH3),His43]hGIP(1-43)-OH(SEQID NO:40);
[A5c11,Cys33(琥珀酰亚胺-N-(CH2)11-CH3),His43]hGIP(1-43)-OH(SEQID NO:41);
[A5c11,Cys43(琥珀酰亚胺-N-(CH2)11-CH3)]hGIP(1-43)-OH(SEQ IDNO:42);
[A5c11,Lys43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH(SEQ ID NO:43);
[A5c11,Orn32(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:44);或
[A5c11,Orn33(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:45)。
4.根据权利要求2的化合物或其可药用盐,其中:
A7是Ile;
A13是Ala或Aib;
A14是Met,A5c,A6c,或Nle;
A31是Gly或缺失;
A35是Asp或缺失;和
A42是Gln或缺失。
5.根据权利要求4的化合物或其可药用盐,其中所述化合物为:
(A5c11,41)hGIP(1-42)-OH(SEQ ID NO:4);
(A5c11,40)hGIP(1-42)-OH(SEQ ID NO:5);
(A5c11,His43)hGIP(1-43)-OH(SEQ ID NO:6);
(A5c11,Asn43)hGIP(1-43)-OH(SEQ ID NO:7);
(Aib13,Asp43)hGIP(1-43)-NH2(SEQ ID NO:8);
(Aib13,Nle14,A5c40)hGIP(1-42)-OH(SEQ ID NO:9);
(Aib13,A5c40)hGIP(1-42)-OH(SEQ ID NO:10);
(A5c11,Ala43)hGIP(1-43)-OH(SEQ ID NO:11);
(Aib13,Nle14,Phe43)hGIP(1-43)-OH(SEQ ID NO:12);
(A5c11,Thr43)hGIP(1-43)-OH(SEQ ID NO:13);
(A6c11,14,41)hGIP(1-42)-OH(SEQ ID NO:14);
(Aib13,Trp43)hGIP(1-43)-OH(SEQ ID NO:15);
(A5c11,Ado43)hGIP(1-43)-OH(SEQ ID NO:16);
(A6c11,14,40)hGIP(1-42)-OH(SEQ ID NO:17);
(A5c11,14,His43)hGIP(1-43)-OH(SEQ ID NO:23);
(A5c11,Nle14,His43)hGIP(1-43)-OH(SEQ ID NO:24);
[A5c11,Orn32(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:25);
[A5c11,Orn33(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:26);
[A5c11,Orn43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH(SEQ ID NO:27);
[A5c11,Cys32(琥珀酰亚胺-N-(CH2)15-CH3),His43]hGIP(1-43)-OH(SEQID NO:28);
[A5c11,Cys33(琥珀酰亚胺-N-(CH2)15-CH3),His43]hGIP(1-43)-OH(SEQID NO:29);
[A5c11,Cys43(琥珀酰亚胺-N-(CH2)15-CH3)]hGIP(1-43)-OH(SEQ IDNO:30);
(A5c11)hGIP(1-30)-NH2(SEQ ID NO:31);
(A5c11,14)hGIP(1-30)-NH2(SEQ ID NO:33);
(A5c11,41,Cys32)hGIP(1-42)-NH2(SEQ ID NO:34);
(A5c11,41,Cys33)hGIP(1-42)-NH2(SEQ ID NO:35);
(A5c11,41,Cys43)hGIP(1-43)-NH2(SEQ ID NO:36);
[A5c11,Orn32(N-C(O)-(CH2)10-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:37);
[A5c11,Orn33(N-C(O)-(CH2)10-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:38);
[A5c11,Lys43(N-C(O)-(CH2)10-CH3)]hGIP(1-43)-OH(SEQ ID NO:39);
[A5c11,Cys32(琥珀酰亚胺-N-(CH2)11-CH3),His43]hGIP(1-43)-OH(SEQID NO:40);
[A5c11,Cys33(琥珀酰亚胺-N-(CH2)11-CH3),His43]hGIP(1-43)-OH(SEQID NO:41);
[A5c11,Cys43(琥珀酰亚胺-N-(CH2)11-CH3)]hGIP(1-43)-OH(SEQ IDNO:42);
[A5c11,Lys43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH(SEQ ID NO:43);
[A5c11,Orn32(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:44);或
[A5c11,Orn33(N-C(O)-(CH2)14-CH3),His43]hGIP(1-43)-OH(SEQ IDNO:45)。
6.根据权利要求2的化合物或其可药用盐,其中:
A7是A6c;
A11是Ser;
A13是Ala;
A14是Met或Nle;
A31是Gly或Orn(N-C(O)-(CH2)12-CH3);
A32是Lys;
A33是Lys;
A35是Asp或Orn(N-C(O)-(CH2)12-CH3);
A40是Ile;
A41是Thr或A6c;
A42是Gln或Cys(Psu);和
A43是缺失。
7.根据权利要求6的化合物或其可药用盐,其中所述化合物为:
[A6c7,Cys(Psu)42]hGIP(1-42)-OH(SEQ ID NO:18);
(A6c7,41)hGIP(1-42)-OH(SEQ ID NO:19);
(A6c7,41,Nle14)hGIP(1-42)-OH(SEQ ID NO:20);
[A6c7,Orn35(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH(SEQ ID NO:21);或
[A6c7,Orn31(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH(SEQ ID NO:22)。
8.根据权利要求1-7中任一项的化合物或其可药用盐,还包含共价连接的PEG基。
9.根据权利要求8的化合物或其可药用盐,其中所述PEG基通过Cys(马来酰亚胺),hCys(马来酰亚胺),或Pen(马来酰亚胺)接头连接至化合物以形成Cys(琥珀酰亚胺-N-PEG),hCys(琥珀酰亚胺-N-PEG),或Pen(琥珀酰亚胺-N-PEG)。
10.根据权利要求9的化合物或其可药用盐,其中所述PEG化发生在16,30,和31-43位的任一氨基酸残基位置,其中Cys(琥珀酰亚胺-N-PEG),hCys(琥珀酰亚胺-N-PEG),或Pen(琥珀酰亚胺-N-PEG)位于16,30,和31-43位的任一氨基酸残基。
11.根据权利要求10的化合物或其可药用盐,其中所述PEG化发生在32,33和43位的任一氨基酸残基,其中Cys(琥珀酰亚胺-N-PEG),hCys(琥珀酰亚胺-N-PEG),或Pen(琥珀酰亚胺-N-PEG)位于32,33和43位的任一氨基酸残基。
12.根据权利要求11的化合物或其可药用盐,其中所述PEG基具有从约2,000至约80,000的平均分子量。
13.根据权利要求12的化合物或其可药用盐,其中所述PEG选自5KPEG,10K PEG,20K PEG,30K PEG,40K PEG,50K PEG,和60K PEG以形成Cys(琥珀酰亚胺-N-5K PEG),Cys(琥珀酰亚胺-N-10K PEG),Cys(琥珀酰亚胺-N-20K PEG),Cys(琥珀酰亚胺-N-30K PEG),Cys(琥珀酰亚胺-N-40KPEG),Cys(琥珀酰亚胺-N-50K PEG),Cys(琥珀酰亚胺-N-60K PEG),hCys(琥珀酰亚胺-N-5K PEG),hCys(琥珀酰亚胺-N-10K PEG),hCys(琥珀酰亚胺-N-20K PEG),hCys(琥珀酰亚胺-N-30K PEG),hCys(琥珀酰亚胺-N-40K PEG),hCys(琥珀酰亚胺-N-50K PEG),hCys(琥珀酰亚胺-N-60KPEG),Pen(琥珀酰亚胺-N-5K PEG),Pen(琥珀酰亚胺-N-10K PEG),Pen(琥珀酰亚胺-N-20K PEG),Pen(琥珀酰亚胺-N-30K PEG),Pen(琥珀酰亚胺-N-40K PEG),或Pen(琥珀酰亚胺-N-50K PEG),或Pen(琥珀酰亚胺-N-60KPEG)。
14.根据权利要求9-13中任一项的化合物或其可药用盐,其中所述琥珀酰亚胺-N-PEG为线性的。
15.根据权利要求14的化合物或其可药用盐,其中所述线性琥珀酰亚胺-N-PEG为琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-PEG。
16.根据权利要求9-13中任一项的化合物或其可药用盐,其中所述琥珀酰亚胺-N-PEG为分支的。
17.根据权利要求16的化合物或其可药用盐,其中所述分支琥珀酰亚胺-N-PEG为琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(PEG)-CH2-PEG。
18.根据权利要求13-17中任一项的化合物或其可药用盐,其中所述化合物为:
[A5c11,41,Cys32(琥珀酰亚胺-N-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:46);
[A5c11,41,Cys33(琥珀酰亚胺-N-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:47);
[A5c11,41,Cys43(琥珀酰亚胺-N-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:48);
[A5c11,41,Cys43(琥珀酰亚胺-N-30K PEG)]hGIP(1-43)-NH2(SEQ ID NO:49);
[A5c11,Nle14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20KPEG)]hGIP(1-43)-NH2(SEQ ID NO:50);
[A5c11,Nle14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20KPEG)]hGIP(1-42)-NH2(SEQ ID NO:51);
[A5c11,Nle14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20KPEG)]hGIP(1-42)-NH2(SEQ ID NO:52);
[A5c11,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-43)-NH2(SEQ ID NO:53);
[A5c11,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:54);
[A5c11,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:55);
[A5c11,Nle14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:56);
[A5c11,Nle14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:57);
[A5c11,Nle14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:58);
[A5c11,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:59);
[A5c11,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:60);
[A5c11,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:61);
[A5c11,14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-43)-NH2(SEQ ID NO:62);
[A5c11,14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:63);
[A5c11,14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:64);
[A5c11,14,Cys43(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:65);
[A5c11,14,Cys32(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:66);或
[A5c11,14,Cys33(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20KPEG)-CH2-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:67)。
19.包含有效量的权利要求1-18中任一项的肽类似物的药物组合物。
20.权利要求19的药物组合物,还包含可药用载体。
21.在需要的受试者中引发GIP受体激动剂效应的方法,其包含对所述受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物。
22.在需要的受试者中引发GIP受体拮抗剂效应的方法,其包含对所述受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物。
23.治疗GIP受体结合介导的病症或疾病的方法,其包含对需要的受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物的步骤。
24.权利要求23的方法,其中所述GIP受体结合介导的病症或疾病选自1型糖尿病、2型糖尿病、肥胖、胰岛素抗性、葡萄糖不耐受、脂肪肝、胰高血糖素瘤、气道分泌紊乱、代谢紊乱、关节炎、骨质疏松、中枢神经系统疾病、再狭窄、神经变性疾病、肾衰竭,充血性心力衰竭,肾病综合症,肝硬化,肺水肿,高血压,和需要降低食物摄取和/或减少体重的疾病。
25.治疗糖尿病的方法,其包含对需要的受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物的步骤。
26.权利要求25的方法,其中所述糖尿病为2型糖尿病。
27.治疗糖尿病相关疾病的方法,其包含对需要的受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物的步骤。
28.权利要求27的方法,其中所述糖尿病相关疾病选自高血糖症,高胰岛素血症,糖耐量降低,空腹血糖异常,血脂异常,高甘油三酯血症和胰岛素抗性。
29.治疗或预防糖尿病继发性原因的方法,其包含对需要的受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物的步骤。
30.权利要求29的方法,其中所述继发性原因选自糖皮质激素过剩,生长激素过量,嗜铬细胞瘤和药物引起的糖尿病。
31.治疗肥胖的方法,其包含对需要的受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物的步骤。
32.在需要的受试者中刺激胰岛素分泌的方法,通过对所述受试者施用治疗有效量的权利要求1-18中任一项的肽类似物或权利要求19或权利要求20的药物组合物。
33.权利要求1-18中任一项的肽类似物在制备用于GIP受体结合以预防或治疗GIP受体类似物结合异常的相关疾病或病症的药物中的用途。
34.根据权利要求33的用途,用于制备预防或治疗胰腺β细胞凋亡的药物。
35.根据权利要求33的用途,用于制备增强胰腺β细胞的葡萄糖依赖性增殖的药物。
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CN107207576A (zh) * | 2015-01-09 | 2017-09-26 | 伊莱利利公司 | Gip和glp‑1共激动剂化合物 |
CN107207576B (zh) * | 2015-01-09 | 2020-11-24 | 伊莱利利公司 | Gip和glp-1共激动剂化合物 |
CN109715662A (zh) * | 2015-12-23 | 2019-05-03 | 美国安进公司 | 使用抑胃肽受体(gipr)结合蛋白与glp-1激动剂的组合来治疗或改善代谢病症的方法 |
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EA201170303A1 (ru) | 2011-10-31 |
AU2009280015A1 (en) | 2010-02-11 |
EP2323678A2 (en) | 2011-05-25 |
US20110144007A1 (en) | 2011-06-16 |
US9072703B2 (en) | 2015-07-07 |
MX2011001030A (es) | 2011-04-26 |
EP2323678A4 (en) | 2013-06-12 |
WO2010016938A2 (en) | 2010-02-11 |
CA2732973A1 (en) | 2010-02-11 |
HK1154790A1 (zh) | 2012-05-04 |
CN103641906A (zh) | 2014-03-19 |
JP2011530507A (ja) | 2011-12-22 |
EP2323678B1 (en) | 2016-03-23 |
JP2014028843A (ja) | 2014-02-13 |
AU2009280015B2 (en) | 2012-11-08 |
KR20110043688A (ko) | 2011-04-27 |
BRPI0917579A2 (pt) | 2016-10-11 |
ES2574835T3 (es) | 2016-06-22 |
WO2010016938A3 (en) | 2010-04-15 |
JP5881659B2 (ja) | 2016-03-09 |
EA020005B1 (ru) | 2014-07-30 |
KR101593155B1 (ko) | 2016-02-12 |
KR20130133104A (ko) | 2013-12-05 |
US20150252093A1 (en) | 2015-09-10 |
KR20150056667A (ko) | 2015-05-26 |
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