CN102171244A - 糖依赖性胰岛素释放肽的类似物 - Google Patents
糖依赖性胰岛素释放肽的类似物 Download PDFInfo
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- CN102171244A CN102171244A CN2009801395142A CN200980139514A CN102171244A CN 102171244 A CN102171244 A CN 102171244A CN 2009801395142 A CN2009801395142 A CN 2009801395142A CN 200980139514 A CN200980139514 A CN 200980139514A CN 102171244 A CN102171244 A CN 102171244A
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Abstract
本发明提供一系列新的糖依赖性胰岛素释放肽的类似物、含有所述化合物的药物组合物、和所述化合物作为GIP-受体激动剂或拮抗剂用于治疗GIP-受体介导的病症例如非胰岛素依赖性糖尿病和肥胖症的用途。
Description
发明领域
本发明涉及以下领域:糖依赖性胰岛素释放肽(glucose-dependent insulinotropic polypeptide)的新类似物、含有所述化合物的药物组合物、和所述化合物作为GIP-受体激动剂或拮抗剂用于治疗GIP-受体介导的病症例如非胰岛素依赖性糖尿病和肥胖症的用途。
背景技术
糖依赖性胰岛素释放多肽(“GIP”,也称为“肠胃抑肽”(gastric inhibitory polypeptide);SEQ ID NO:1)是由小肠的肠内分泌K-细胞响应于口服营养素摄入而分泌到血流中的42-残基肽。GIP抑制胃酸的分泌,且其显示为口服葡萄糖摄入之后从胰腺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)。
由摄入葡萄糖和其它营养素而诱导的胰岛素释放归因于激素和神经的因素(Creutzfeldt,W.等人,1985,Diabetologia,28:565-573)。数种胃肠道调节肽已被推荐为肠降血糖素,在这些候选物中,仅GIP和胰高血糖素样肽1(“GLP-1”)看起来满足要求,被认为是餐后胰岛素释放的生理学刺激剂(Nauck等人,1989,J.Clin.Endorinol.Metab.,69:654-662)。已经证实,GIP和GLP-1的组合效应足以解释肠胰岛轴的整个肠降血糖素效应(Fehmann,H.C.等人,1989,FEBS Lett.,252:109-112)。
如本领域技术人员众所周知,GIP的已知和潜在用途是多种多样和多方面的。因此,施用本发明的化合物以引发激动剂效应,可具有与GIP自身相同的效应和用途。GIP的这些不同用途可总结如下:治疗选自以下的疾病: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)、肥胖症(Green,B.D.等人,2004,Current Pharmaceutical 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、低血糖症、和其中期望食物摄入减少和体重减轻的病症。在胰岛中,GIP不仅急剧增加胰岛素分泌,而且其还通过促进胰岛素原转录和翻译而刺激胰岛素产生(Wang等人,1996,Mol.Cell.Endocrinol.,116:81-87),并增加胰腺β细胞的生长和存活(Trumper等人,2003,Diabetes,52:741-750)。除作用于胰腺以增加胰岛素分泌之外,GIP还直接对胰岛素靶组织产生效应以降低血浆葡萄糖;增加脂肪组织(Eckel等人,1979,Diabetes,28:1141-1142)和肌肉(O’Harte等人,1998,J.Endocrinol.,156:237-243)中的葡萄糖摄入、以及抑制肝脏葡萄糖生成(Elahi,D.等人,1986,Can.J.Physiol.Pharmacol.,65:A18)。
此外,依据本发明的GIP受体拮抗剂可以抑制、阻断或减少自动物肠道的葡萄糖吸收。依据此项观察,可在具有非胰岛素依赖性糖尿病的患者中使用含有GIP拮抗剂的治疗组合物,以在哺乳动物例如人中提高对口服葡萄糖的耐性,从而通过抑制、阻断或减少从哺乳动物肠的葡萄糖吸收而预防、抑制或减少肥胖症。
然而,未修饰GIP作为治疗剂的用途受约2分钟的短暂体内半衰期限制(Said和Mutt,1970,Science,169:1217-1218)。血清中,两种肠降血糖素GIP和GLP-1被二肽基肽酶IV(“DPPIV”)降解。提高GIP抗蛋白水解的稳定性不仅维持GIP对其受体的活性,而且更重要的是,预防GIP片段的生成,其中一些片段起GIP受体拮抗剂的作用(Gault等人,2002,J.Endocrinol.,175:525-533)。所报导的修饰已包括通过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)而保护GIP的N端不被DPPIV蛋白水解。
已递交了涉及GIP类似物对不同靶器官功能的影响及其用作治疗剂的潜在用途的下述专利申请:
PCT公布WO 00/58360公开了刺激胰岛素释放的GIP的肽基类似物。特别是,该申请公开了包含来自GIP(1-42)N末端的至少15个氨基酸残基的特定肽基类似物,例如在1、2和3位含有确切地一个氨基酸置换或修饰的GIP类似物,例如[Pro3]GIP(1-42)。
PCT公布WO 98/24464公开了GIP的拮抗剂(其主要由对应于GIP序列的位置7-30的24个氨基酸的多肽组成)、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性的方法。
PCT公布WO 03/082898公开了GIP的C端截短片段和N端修饰类似物,以及其中肽键被减少或接近DPPIV特异性切割位点的氨基酸被改变的各种GIP类似物。该申请还公开了在GIP的潜在受体结合位点之间具有不同接头的类似物。该申请的化合物被认为对治疗GIP-受体介导的病症例如非胰岛素依赖性糖尿病和肥胖症有用。
对如下改良的GIP类似物存在需求,其在制剂中稳定、且由于降低的蛋白水解敏感性和减少的清除而具有长的体内血浆半衰期,然而仍保持对GIP受体的结合亲和力以引发相应的激动或拮抗效应。而且,除了如本文示例的本发明化合物的其它疗效之外,对血浆葡萄糖水平的更紧密控制可以防止长期糖尿病并发症,由此为患者提供改善的生活质量。
发明概述
一方面,本发明涉及下式(I)的GIP的肽变体:
(R2R3)-A1-A2-A3-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:
A1是Tyr、4Hppa、或HN-CH((CH2)n-N(R4R5))-C(O);
A2是Ala、Abu、D-Abu、Acc、Aib、β-Ala、D-Ala、Gaba、Gly、Ser、D-Ser、Thr、D-Thr、Val或D-Val;
A3是Glu、Aib、Asp、NMe-Asp、Dhp、Dmt、Glu、NMe-Glu、3Hyp、4Hyp、4Ktp、Pro、hPro、Thz或Tic;
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、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、Acc或Aib;
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、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、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、Acc、Aib、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、Aib、Ala、Asp、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)烃部分,且Z0是H、OH、CO2H或CONH2;
R2、R3、R4和R5各自独立地选自由以下组成的组:H、(C1-C30)烷基、(C1-C30)杂烷基、(C1-C30)酰基、(C2-C30)链烯基、(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)链烯基、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;条件是,当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)酰基时,R3是H、(C1-C30)烷基、(C1-C30)杂烷基、(C2-C30)链烯基、(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)链烯基、取代的(C2-C30)炔基或取代的芳基(C1-C30)烷基;进一步条件是,当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)酰基时,R5是H、(C1-C30)烷基、(C1-C30)杂烷基、(C2-C30)链烯基、(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)链烯基、取代的(C2-C30)炔基或取代的芳基(C1-C30)烷基;
n每次出现时均独立地是1至5(包括1和5)的整数;
s、t、x和y各自在每次出现时均独立地是1至30(包括1和30)的整数;
X4、X5、X6、X7和X8各自在每次出现时均独立地是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;且
条件是当A1是4Hppa时,R2和R3缺失;
进一步条件是,该化合物的1、2或3位上仅一个氨基酸被置换或修饰;且
进一步条件是,式(I)化合物不是(D-Ala2)hGIP(1-42)、(Pro3)hGIP(1-42)(SEQ ID NO:120)、(Aib3)hGIP(1-42)(SEQ ID NO:121)、(Ser2)hGIP(1-42)(SEQ ID NO:122)、(Abu2)hGIP(1-42)(SEQ ID NO:123)、(D-Abu2)hGIP(1-42)、(D-Ser2)hGIP(1-42)、(D-Thr2)hGIP(1-42)或(D-Val2)hGIP(1-42)。
由上式(I)涵盖的化合物的子集(A)是这样的化合物,其中:
A1是Tyr、4Hppa或Orn(N-C(O)-(CH2)12-CH3);
A2是Ala、A5c、A6c、Aib、D-Ala、Gly或Ser;
A3是Glu、Dhp、3Hyp、4Hyp、Pro、hPro或Tic;
A4是Gly或Aib;
A5是Thr、A5c或Aib;
A6是Phe或A6c;
A7是Ile、A5c、A6c或Aib;
A8是Ser或Aib;
A9是Asp或Aib;
A10是Tyr;
A11是Ser、A5c、A6c、Aib或Nle;
A12是Ile、A5c或Aib;
A13是Ala或Aib;
A14是Met、A5c、A6c或Nle;
A15是Asp;
A16是Lys;
A17是Ile或A6c;
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或A6c;
A27是Leu或A6c;
A28是Ala或Aib;
A29是Gln;
A30是Lys;
A31是Gly、Aib、Cys(Psu)、His或缺失;
A32是Lys、Cys(Psu)或缺失;
A33是Lys、Cys(Psu)或缺失;
A34是Asn、Cys(Psu)或缺失;
A35是Asp、Cys(Psu)或缺失;
A36是Trp、Cys(Psu)或缺失;
A37是Lys、Cys(Psu)或缺失;
A38是His、Cys(Psu)或缺失;
A39是Asn、Cys(Psu)或缺失;
A40是Ile、A5c、A6c、Cys(Psu)或缺失;
A41是Thr、A5c、A6c、Aib、Cys(Psu)或缺失;
A42是Gln或缺失;
A43是Cys(Psu)、Gln、His或缺失;且
条件是,该化合物在位置4-43包含至少一个另外的氨基酸置换或修饰。
前述子集(A)的化合物的一个子集是这样的化合物,其中:A2是D-Ala。
前述子集(A)的化合物的另一个子集是这样的化合物,其中:A31至A43缺失。
前述子集(A)的化合物的另一个子集是这样的化合物,其中:A2是Ala、A5c、A6c或Gly;且A3是Glu、Dhp、3Hyp、4Hyp、hPro或Tic。
本发明的另一方面涵盖主要由来自天然hGIP氨基酸序列N端的前30个连续氨基酸残基的序列组成的化合物,其中该序列包含在2位上的A5c、A6c、Aib、D-Ala、Gly或Ser置换,和在位置3-30上的至少一个另外的氨基酸置换或修饰。
紧前一方面的本发明化合物的一个子集是这样的化合物,其中A2是Aib;A3是Pro;且A7、A11、A13和A14中的至少一个不是天然GIP中相应位置的氨基酸残基。
本发明的另一方面涵盖GIP类似物,其包含在2位上的A5c、A6c、Aib、D-Ala、Gly或Ser置换,和在位置1和3-42上的至少一个另外的氨基酸置换或修饰。
紧前一方面的本发明化合物的一个子集是这样的化合物,其中:A2是Aib。
优选的式(I)化合物是:
实施例1:(Aib2,11)hGIP(1-42)-OH(SEQ ID NO:4);
实施例2:(Aib2,9)hGIP(1-42)-OH(SEQ ID NO:5);
实施例3:(Aib2,7)hGIP(1-42)-OH(SEQ ID NO:6);
实施例4:(Aib2,5)hGIP(1-42)-OH(SEQ ID NO:7);
实施例5:(Aib2,A5c5)hGIP(1-42)-OH(SEQ ID NO:8);
实施例6:(Aib2,A5c7)hGIP(1-42)-OH(SEQ ID NO:9);
实施例7:(Aib2,A5c12)hGIP(1-42)-OH(SEQ ID NO:10);
实施例8:(Aib2,12)hGIP(1-42)-OH(SEQ ID NO:11);
实施例9:(Aib2,8)hGIP(1-42)-OH(SEQ ID NO:12);
实施例10:(Aib2,4)hGIP(1-42)-OH(SEQ ID NO:13);
实施例11:(Aib2,A5c5)hGIP(1-30)-NH2(SEQ ID NO:14);
实施例12:(Aib2,A5c7)hGIP(1-30)-NH2(SEQ ID NO:15);
实施例13:(Aib2,A5c12)hGIP(1-30)-NH2(SEQ ID NO:16);
实施例14:(Aib2,4)hGIP(1-30)-NH2(SEQ ID NO:17);
实施例15:(Aib2,5)hGIP(1-30)-NH2(SEQ ID NO:18);
实施例16:(Aib2,7)hGIP(1-30)-NH2(SEQ ID NO:19);
实施例17:(Aib2,8)hGIP(1-30)-NH2(SEQ ID NO:20);
实施例18:(Aib2,9)hGIP(1-30)-NH2(SEQ ID NO 21);
实施例19:(Aib2,11)hGIP(1-30)-NH2(SEQ ID NO:22);
实施例20:(Aib2,12)hGIP(1-30)-NH2(SEQ ID NO:23);
实施例21:(Aib2,13,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:24);
实施例22:(Aib2,31,A6c7)hGIP(1-42)-OH(SEQ ID NO:25);
实施例23:(Aib2,41,A6c7)hGIP(1-42)-OH(SEQ ID NO:26);
实施例24:(Aib2,31,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:27);
实施例25:(Aib2,41,A6c7,Nle14)hGIP(1-42)-OH(SEQ IF NO:28);
实施例26:(Aib2,A6c7,26,Nle14)hGIP(1-42)-OH(SEQ ID NO:29);
实施例27:(Aib2,A6c7,27,Nle14)hGIP(1-42)-OH(SEQ ID NO:30);
实施例28:(Aib2,A6c7,40,Nle14)hGIP(1-42)-OH(SEQ ID NO:31);
实施例29:(Aib2,A6c7,41,Nle14)hGIP(1-42)-OH(SEQ ID NO:32);
实施例30:(Aib2,28,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:33);
实施例31:(Aib2,A6c7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:34);
实施例32:(Aib2,A5c7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:35);
实施例33:(Aib2,11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:36);
实施例34:(A5c2,7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:37);
实施例35:(Aib2,A5c7,14)hGIP(1-30)-NH2(SEQ ID NO:38);
实施例36:(A6c2,7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:39);
实施例37:(Aib2,A6c7,17,Nle14)hGIP(1-42)-OH(SEQ ID NO:40);
实施例38:(Aib2,11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:41);
实施例39:(Aib2,A6c7,14)hGIP(1-30)-NH2(SEQ ID NO :42);
实施例40:(A5c2,Nle14)hGIP(1-42)-OH(SEQ ID NO:43);
实施例41:(Aib2,11,A6c14)hGIp(1-2)-OH(SEQ ID NO:44);
实施例42:(Aib2,A6c14)hGIP(1-42)-OH(SEQ ID NO:45);
实施例43:(Aib2,A6c7)hGIP(1-42)-OH(SEQ ID NO:46);
实施例44:(Aib2,A5c7,A6c14)hGIP(1-42)-OH(SEQ ID NO:47);
实施例45:(Aib2,11,Nle14)hGIP(1-42)-OH(SEQ ID NO:48);
实施例46:(Aib2,A5c11)hGIP(1-30)-NH2(SEQ ID NO:49);
实施例47:(Aib2,13)hGIP(1-30)-NH2(SEQ ID NO:50);
实施例48:(Aib2,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:51);
实施例49:(Aib2,13,Nle14)hGIP(1-30)-NH2(SEQ ID NO:52);
实施例50:(Aib2,A5c11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:53);
实施例51:(Aib2,A6c7,14)hGIP(1-42)-OH(SEQ ID NO:54);
实施例52:(Aib2,A6c7)hGIP(1-30)-NH2(SEQ ID NO:55);
实施例53:(Aib2,A5c11)hGIP(1-42)-OH(SEQ ID NO:56);
实施例54:(Aib2,A5c11,Nle14)hGIP(1-42)-OH(SEQ ID NO:57);
实施例55:(Aib2,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:58);
实施例56:(A5c2,7,A6c14)hGIP(1-42)-OH(SEQ ID NO:59);
实施例57:(Aib2,13,Nle14)hGIP(1-42)-OH(SEQ ID NO:60);
实施例58:(Aib2,A5c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:61);
实施例59:(Aib2,A5c7,14)hGIP(1-42)-OH(SEQ ID NO:62);
实施例60:(Aib2,13)hGIP(1-42)-OH(SEQ ID NO:63);
实施例61:(Aib2,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:64);
实施例62:(Pro3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:65);
实施例63:(hPro3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO :66);
实施例64:(Dhp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:67);
实施例65:(hPro3,Aib13)hGIP(1-42)-OH(SEQ ID NO:68);
实施例66:(Tic3,Aib13)hGIP(1-42)-OH(SEQ ID NO:69);
实施例67:(4Hyp3,Aib13)hGIP(1-42)-OH(SEQ ID NO:70);
实施例68:(4Hyp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:71);
实施例69:(Tic3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:72);
实施例70:(3Hyp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:73);
实施例71:(Tic3,A6c14)hGIP(1-42)-OH(SEQ ID NO:74);
实施例72:(hPro3,A6c14)hGIP(1-42)-OH(SEQ ID NO:75);
实施例73:[Aib2,A6c7,Cys(Psu)41]hGIP(1-42)-OH(SEQ ID NO:76);
实施例74:(hPro3,A5c11)hGIP(1-42)-OH(SEQ ID NO:77);
实施例75:(Pro3,Aib13)hGIP(1-42)-OH(SEQ ID NO:78);
实施例76:(Pro3,A5c7,14)hGIP(1-42)-OH(SEQ ID NO:79);
实施例77:(Pro3,A5c11)hGIP(1-42)-OH(SEQ ID NO:80);
实施例78:[Aib2,A6c7,Cys(Psu)40]hGIP(1-42)-OH(SEQ ID NO:81);
实施例79:[Aib2,A6c7,Cys(Psu)19]hGIP(1-42)-OH(SEQ ID NO:82);
实施例80:[Aib2,A6c7,Cys(Psu)38]hGIP(1-42)-OH(SEQ ID NO:83);
实施例81:[Aib2,A6c7,Cys(Psu)36]hGIP(1-42)-OH(SEQ ID NO:84);
实施例82:(Tic3,A5c11)hGIP(1-42)-OH(SEQ ID NO:85);
实施例83:(hPro3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:86);
实施例84:(4Hyp3,A6c14)hGIP(1-42)-OH(SEQ ID NO:87);
实施例85:[Aib2,A6c7,Cys(Psu)35]hGIP(1-42)-OH(SEQ ID NO:88);
实施例86:[Aib2,A6c7,Cys(Psu)34]hGIP(1-42)-OH(SEQ ID NO:89);
实施例87:(4Hyp3,A5c11)hGIP(1-42)-OH(SEQ ID NO:90);
实施例88:(4Hyp3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:91);
实施例89:(Tic3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:92);
实施例90:[Aib2,A6c7,Cys(Psu)31]hGIP(1-42)-OH(SEQ ID NO:93);
实施例91:(Pro3,A6c14)hGIP(1-42)-OH(SEQ ID NO:94);
实施例92:(Pro3,A5c11,Nle14)hGIP(1-30)-OH(SEQ ID NO:95);
实施例93:(Aib2,A6c7,Gln43)hGIP(1-43)-OH(SEQ ID NO:96);
实施例94:[Aib2,A6c7,Cys(Psu)32]hGIP(1-42)-OH(SEQ ID NO:97);
实施例95:[Aib2,A6c7,Cys(Psu)43]hGIP(1-43)-OH(SEQ ID NO:98);
实施例96:(Pro3,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:99);
实施例97:(Pro3,A6c7)hGIP(1-30)-NH2(SEQ ID NO:100);
实施例98:(Pro3,A5c11)hGIP(1-30)-NH2(SEQ ID NO:101);
实施例99:[Aib2,A6c7,Cys(Psu)33]hGIP(1-42)-OH(SEQ ID NO:102);
实施例100:[Aib2,A6c7,Cys(Psu)37]hGIP(1-42)-OH(SEQ ID NO:103);
实施例101:(4Hppa1,Aib13)hGIP(1-42)-OH(SEQ ID NO:104);
实施例102:(Pro3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:105);
实施例103:[Orn1(N-C(O)-1(CH2)12-CH3),A6c7]hGIP(1-42)-OH(SEQ ID NO:106);
实施例104:(D-Ala2,A5c11,40)hGIP(1-42)-OH;
实施例105:(D-Ala2,A5c11,His43)hGIP(1-43)-OH;
实施例106:(D-Ala2,A5c11,41)hGIP(1-42)-OH;
实施例107:(D-Ala2,A6c11,14,41)hGIP(1-42)-OH;
实施例108:(Aib2,13,Pro3,Nle14)hGIP(1-30)-NH2(SEQ ID NO:107);
实施例109:(Aib2,Pro3,A6c7)hGIP(1-30)-NH2(SEQ ID NO:108);
实施例110:(Aib2,Pro3,A5c11)hGIP(1-30)-NH2(SEQ ID NO:109);
实施例111:(Aib2,Pro3,A5c11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:110);
实施例112:(Aib2,Pro3,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:111);
实施例113:(NMe-Tyr1,Aib2,A5c11,Nle14)hGIP(1-42)-OH(SEQ ID NO:112);
实施例114:(Gly2,A6c11,14,41)hGIP(1-42)-OH(SEQ ID NO:113);
实施例115:(Gly2,Aib13,A5c40)hGIP(1-42)-OH(SEQ ID NO:114);
实施例116:(Gly2,A5c11,41)hGIP(1-42)-OH(SEQ ID NO:115);
实施例117:(Gly2,A5c11,His43)hGIP(1-43)-OH(SEQ ID NO:116);
实施例118:(Gly2,A5c11,Nle14,His43)hGIP(1-43)-OH(SEQ ID NO:117);
实施例119:(D-Ala2,A5c11,Nle14,His43)hGIP(1-43)-OH;
实施例120:(D-Ala2,A5c11,14,His43)hGIP(1-43)-OH;
实施例121:(D-Ala2,A5c11,14)hGIP(1-30)-NH2;
实施例122:(D-Ala2,A5c11,His31)hGIP(1-31)-NH2;和
实施例123:(Aib2,A5c11,14,His43)hGIP(1-43)-OH(SEQ ID NO:118)。
根据本发明的另一方面,如上文所概述和所附权利要求中所要求保护的本发明化合物还可包含共价连接的PEG部分,其中所述PEG部分通过Cys(马来酰亚胺)、hCys(马来酰亚胺)或Pen(马来酰亚胺)连接体与该化合物共价连接,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”是如下文定义的直链或支链。该PEG部分具有约2,000至约80,000的平均分子量,优选该PEG部分选自由以下组成的组: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-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-40K PEG)、Cys(琥珀酰亚胺-N-50KPEG)、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-5KPEG)、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化在氨基酸残基位置16、30和31-43中的任何一个上发生,优选在氨基酸残基位置32、33和43中的任何一个上发生,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)被放入该氨基酸残基位置之任何一个中。
此外,可以扩展上式(I)以在位置A44-A47上提供PEG化位点。此类PEG化的本发明化合物的C端可以被酰胺化,例如(Aib2,11)hGIP(1-42)-NH2(SEQ ID NO:119)或其可保留为游离酸,例如(Aib2,11)hGIP(1-42)-OH(SEQID NO:4)。
发明详述
本申请采用下面普遍理解的缩写:
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-氨基茚满-2-羧酸
Ala或A:丙氨酸
β-Ala:β-丙氨酸
Amp:4-氨基-苯丙氨酸;
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-氨基十一烷酸
Ava:5-氨基戊酸
Cha:β-环己基丙氨酸
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-羟基苯基)丙酸
3Hyp:3-羟基脯氨酸
4Hyp:4-羟基脯氨酸
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-吡啶基)丙氨酸
3Pal或3-Pal:β-(3-吡啶基)丙氨酸
4Pal或4-Pal:β-(4-吡啶基)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
本文所用的某些其它缩写如下所定义:
Acn:乙腈
Boc:叔丁基氧基羰基
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:电喷雾离子化
Fmoc:9-芴基甲氧基羰基
HOBt:1-羟基苯并三唑
HPLC:高效液相色谱法
IBMX:异丁基甲基黄嘌呤
LC-MS:液相色谱法-质谱法
Mtt:甲基三苯甲基
NMP:N-甲基吡咯烷酮
5K PEG:平均总分子量为约5,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
10K PEG:平均总分子量为约10,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
20K PEG:平均总分子量为约约20,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
30K PEG:平均总分子量为约30,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
40K PEG:平均总分子量为约40,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
50K PEG:平均总分子量为约50,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
60K PEG:平均总分子量为约60,000的聚乙二醇,其可包括其它官能团或部分例如连接体,且其是如下文定义的直链或支链,
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-CH3)”具有结构:
其中,x=1-30,且y=1-30。
“hCys(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”具有结构:
其中,x=1-30,且y=1-30。
“Pen(琥珀酰亚胺-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”具有结构:
其中,x=1-30,且y=1-30。
“Cys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”具有结构:
其中,s=1-30,且t=1-30。
“hCys(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”具有结构:
其中s=1-30,且t=1-30。
“Pen(琥珀酰亚胺-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”具有结构:
其中s=1-30,且t=1-30。
“Cys(琥珀酰亚胺-N-PEG)”具有结构:
“Cys(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-PEG)”具有结构:
“Cys(琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(PE G)-CH2-PEG)”具有结构:
除N端氨基酸之外,本公开内容中的所有氨基酸缩写(例如Ala)代表-NH-C(R)(R′)-CO-的结构,其中R和R′各自独立地是氢或氨基酸侧链(例如就Ala而言,R=CH3且R′=H)或R和R′可结合形成环系统。就N端氨基酸而言,该缩写代表(R2R3)N-C(R)(R′)-CO-的结构,其中R2和R3如上式(I)中所定义。
术语“(C1-C30)烃部分”包括烷基、链烯基和炔基,在链烯基和炔基的情况下为C2-C30。
本发明的肽在本文也由另一种形式表示,例如(A5c2)hGIP(1-42)-OH(SEQ ID NO:3),其中相对于天然序列的替代氨基酸置于方括号内(例如A5c2替代hGIP中的Ala2)。圆括弧之间的数字是指存在于肽中的氨基酸的编号(例如hGIP(1-42)-OH(SEQ ID NO:1)是hGIP的肽序列的氨基酸1-42)。hGIP(1-30)-NH2(SEQ ID NO:2)中的称谓“NH2”表示肽的C端被酰胺化;hGIP(1-42)(SEQ ID NO:1)或hGIP(1-42)-OH(SEQ ID NO:1)意指C端是游离酸。
人GIP(“hGIP”)具有以下氨基酸序列:
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”是指R″-C(O)-,其中R″是H、烷基、取代的烷基、杂烷基、取代的杂烷基、链烯基、取代的链烯基、芳基、烷基芳基或取代的烷基芳基。
“烷基”是指含有一个或多个碳原子的烃基,其中多个碳原子(如果存在)通过单键连接。烷基烃基团可以是直链或含有一个或多个支链或环状基团。
“取代的烷基”是指这样的烷基,其中该烃基的一个或多个氢原子被一个或多个选自由以下组成的组的取代基替代:卤素(即氟、氯、溴和碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、卤素取代的-C1-20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的存在引起烷基酸的产生。含有-(CH2)0-20-COOH或由之组成的烷基酸的实例包括2-降冰片烷乙酸、叔丁酸和3-环戊基丙酸。
“杂烷基”是指这样的烷基,其中该烃基中的一个或多个碳原子被一个或多个以下基团替代:氨基、酰胺基、-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”是指这样的杂烷基,其中该烃基的一个或多个氢原子被一个或多个选自由以下组成的组的取代基替代:卤素、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、被卤素取代的-C1-20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。
“链烯基”是指由两个或多个碳构成的烃基,其中存在一个或多个碳-碳双键。链烯基烃基可以是直链或含有一个或多个支链或环状基团。
“取代的链烯基”是指其中一个或多个氢被一个或多个选自由以下组成的组的取代基替代的链烯基:卤素、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、被卤素取代的-C1-20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”是指任选取代的芳族基团,有至少一个具有共轭π电子体系的环,含有至多三个共轭或稠合的环体系。芳基包括碳环芳基、杂环芳基和联芳基。优选地,芳基是5或6元环。优选的杂环芳基的原子是一个或多个硫、氧和/或氮。芳基的实例包括苯基、1-萘基、2-萘基、吲哚、喹啉、2-咪唑和9-蒽。芳基取代基可以选自由以下组成的组:-C1-20烷基、-C1-20烷氧基、卤素、-OH、-CN、-SH、-NH2、-NO2、被卤素取代的-C1-20烷基、-CF3、-OCF3和-(CH2)0-20-COOH。在不同的实施方案中,芳基含有0、1、2、3或4个取代基。
“烷芳基”是指连接“烷基”的“芳基”。
合成
本发明的肽可以通过标准固相肽合成法制备。例如,参见Stewart,J.M.等人,1984,Solid Phase Synthesis,Pierce Chemical Co.,第2版。如果R1是NH-X2-CH2-CONH2,即Z0=CONH2,那么肽的合成以与Rink酰胺MBHA树脂偶联的Fmoc-HN-X2-CH2-CONH2开始。如果R1是NH-X2-CH2-COOH,即Z0=COOH,那么肽的合成以与Wang树脂偶联的Fmoc-HN-X2-CH2-COOH开始。对于此特定步骤,使用2摩尔当量的Fmoc-HN-X2-COOH、HBTU和HOBt与10摩尔当量的DIPEA。偶联时间是约8小时。
在含有A5c、A6c、和/或Aib的本发明GIP类似物的合成中,对于这些残基以及紧随它们的残基,偶联时间是2小时。
上述通式的取代基R2和R3可通过本领域已知的标准方法与N端氨基酸A1的游离胺连接。例如,烷基例如(C1-C30)烷基可用还原性烷基化来连接。羟烷基例如(C1-C30)羟基烷基也可用还原性烷基化来连接,其中游离羟基用叔丁酯保护。酰基,例如-C(O)X3,可通过将完成的树脂与3摩尔当量的游离酸和二异丙基碳二亚胺在二氯甲烷中混合约1小时而将游离酸如-X3COOH与N端氨基酸的游离胺偶联,以实现连接。如果游离酸含有游离羟基,例如3-氟-4-羟基苯乙酸,那么偶联的进行应还用3摩尔当量HOBT。
以下实施例描述了用于制备本发明肽的合成方法,该方法对本领域技术人员而言是熟知的。其它方法也为本领域技术人员所知。为了举例说明目的提供了实施例,但是实施例并不意味着以任何方式限制本发明的范围。
实施例73:[Aib
2
,A6c
7
,Cys(Psu)
41
]hGIP(1-42)-OH
采用微波辅助的Fmoc化学,以0.1mmol规模,在Liberty肽合成仪(CEM;Matthews,NC,USA)上,使用固相肽合成来装配肽。使用预装载的Fmoc-Gln(Trt)-Wang树脂(0.59mmol/g;Novabiochem,San Diego,CA,USA)产生C端酸肽。将树脂(0.17g)和15ml二甲基甲酰胺(DMF)放置在50ml锥形管中,并装载到合成仪中的树脂位置上。然后经自动化过程将树脂定量转移到反应容器中。使用0.1mmol规模合成的标准Liberty合成方案。该方案包括:通过用7ml 20%在DMF中的哌啶(含有0.1M N-羟基苯并三唑(HOBT))初步处理,将N端Fmoc部分脱保护。在微波功率(45瓦特,最大温度75℃)和鼓入氮气(开3秒/关7秒)下,初始的脱保护步骤为30秒。然后将反应容器排干,进行与第一处理相同的第二哌啶处理,除了持续时间为3分钟之外。然后将树脂排干,用DMF彻底洗涤数次。然后加入制备成DMF中的0.2M储备液的经保护的氨基酸Fmoc-Thr(tBu)-OH(2.5ml,5当量),之后加入1.0ml 0.45M(4.5当量)在DMF中的HBTU[2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐]。随后加入0.5ml 2M(10当量)在NMP(N-甲基吡咯烷酮)中的DIPEA(二异丙基乙胺)。用20瓦特的微波功率(最大温度75℃)和相同的氮气鼓入速率进行偶联步骤5分钟。
初始的偶联步骤后,将反应容器排出废物,并重复偶联步骤。然后类似于循环1,启动循环2。类似地引入所有氨基酸,在整个序列中采用双偶联策略。循环1-3、19-20、25-26和30-39含有紧随偶联步骤的加帽程序。使用如下多步骤微波方案,通过加入7ml 0.5M乙酸酐(含有0.015M在NMP中的HOBT)和2ml 2M DIPEA溶液,进行加帽:50瓦特的功率进行30秒(最大温度为65℃)、随后微波功率关闭30秒、之后开启第二轮的30秒微波功率(50瓦特)、然后再30秒的微波功率关闭。然后排干树脂,用DMF彻底洗涤。使用以下氨基酸(Advanced Chemtech;Louisville,KY,USA):循环1:Fmoc-Cys(Trt)-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稍加修改的版本。前2分钟微波功率关闭,然后微波功率开启4分钟(20瓦特;最大温度为50℃)。一旦肽主链完成,采用标准哌啶处理以去除N端Fmoc基团。用DMF彻底洗涤树脂,然后使用DMF作为转移溶剂将树脂转移回到50ml锥形管中。
将树脂脱保护,通过用5ml下述试剂处理从树脂切下:5%TIS、2%水、5%(w/v)二硫苏糖醇(DTT)、88%TFA,允许混合3.5小时。将滤液收集到45ml冷无水乙醚中。在冷冻离心机中以3500RPM离心10分钟将沉淀物沉淀。倾析乙醚,将肽再悬浮于新鲜乙醚中。总共进行2次乙醚后处理。最后一次乙醚洗涤后,将肽空气干燥以去除残余乙醚。将肽沉淀物再悬浮于8ml乙腈(Acn)中,然后加入8ml去离子水,使其完全溶解。然后用质谱法分析肽溶液。采用电喷雾离子化进行质量分析,鉴定了含有5011.7道尔顿质量的主产物;相应于该期望的线性产物。粗产物(约500mg)进行了HPLC分析,其中采用250×4.6mm C18柱(Phenomenex;Torrance,CA,USA)并用2-80%乙腈(0.1%TFA)的梯度,历经30分钟。分析性HPLC鉴定了具有34%纯度的产物。然后将粗肽在配备有C18反相柱的制备性HPLC上纯化,其中用10-60%乙腈(0.1%TFA)以10ml/min流速进行50分钟。然后将纯化肽冷冻干燥,得到15mg肽。然后用N-丙基马来酰亚胺(Pma)将线性肽衍生化,以在半胱氨酸侧链上产生丙基琥珀酰亚胺(Psu)衍生物。将经纯化的线性肽以5mg/ml溶于水(用碳酸铵调节至pH 6.5)中。加入5当量的Pma,连续搅拌30秒。然后用质谱法分析衍生化的肽溶液。电喷雾离子化进行质量分析,鉴定了含有5150.7道尔顿质量的主产物;相应于所需Psu衍生的产物。然后用与上述类似的梯度,通过制备性HPLC将产物重纯化。用HPLC和质谱法对纯化产物进行分析:纯度为95.10%和5150.9道尔顿,随后冷冻干燥。冻干后,
实施例103:[Orn
1
(N-C(O)-(CH
2
)
12
-CH
3
),A6c
7
]hGIP(1-42)-OH
采用微波辅助的Fmoc化学,以0.1mmol规模,在Liberty肽合成仪(CEM;Matthews,NC,USA)上,使用固相肽合成来装配肽。使用预装载的Fmoc-Gln(Trt)-Wang树脂(0.59mmol/g;Novabiochem,San Diego,CA,USA)产生该C端酸肽。将树脂(0.17g)和15ml二甲基甲酰胺(DMF)放置在50ml锥形管中,并装载到合成仪中的树脂位置上。然后经自动化过程将树脂定量转移到反应容器中。使用0.1mmol规模合成的标准Liberty合成方案。该方案包括:通过用7ml 20%在DMF中的哌啶(含有0.1M N-羟基苯并三唑(HOBT))初步处理,将N端Fmoc部分脱保护。在微波功率(45瓦特,最大温度为75℃)和鼓入氮气(开3秒/关7秒)下,初始的脱保护步骤为30秒。然后将反应容器排干,进行与第一处理相同的第二哌啶处理,除了持续时间为3分钟之外。然后将树脂排干,用DMF彻底洗涤数次。然后加入制备成DMF中的0.2M储备液的经保护的氨基酸Fmoc-Thr(tBu)-OH(2.5ml,5当量),之后加入1.0ml 0.45M(4.5当量)在DMF中的HBTU[2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐]。随后加入0.5ml 2M(10当量)在NMP(N-甲基吡咯烷酮)中的DIPEA(二异丙基乙胺)。用20瓦特的微波功率(最大温度为75℃)和相同的氮气鼓入速率进行偶联步骤5分钟。
初始的偶联步骤后,将反应容器排出废物,并重复偶联步骤。然后类似于循环1,启动循环2。类似地引入所有氨基酸,在整个序列中采用双偶联策略。循环1-3、19-20、25-26和30-39含有紧随偶联步骤的加帽程序。使用以下多步骤微波方案,通过加入7ml 0.5M乙酸酐(含有0.015M在NMP中的HOBT)和2ml 2M DIPEA溶液,进行加帽:50瓦特的功率进行30秒(最大温度为65℃)、随后微波功率关闭30秒、之后开启第二轮的30秒微波功率(50瓦特)、然后再次微波功率关闭30秒。然后排干树脂,用DMF彻底洗涤。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稍加修改的版本。前2分钟微波功率关闭,然后微波功率开启4分钟(20瓦特;最大温度为50℃)。一旦肽主链完成,在5秒开和10秒关的N2喷吹率(sparge rate)下,用12ml在二氯甲烷(DCM)中的1%三氟乙酸(TFA)/5%三异丙基硅烷(TIS)处理树脂5分钟。然后排干树脂,再用DCM溶液中的1%TFA/5%TIS处理5分钟。这总共进行7次,以有效去除来自鸟氨酸侧链的Mtt部分。用DMF彻底洗涤树脂数次,然后用标准哌啶处理以便中和鸟氨酸的δN上的残余TFA盐。肉豆蔻酸(CH3-(CH2)12-COOH;Aldrich,St.Louis,MO,USA)被制备成0.2M在DMF中的溶液,使用标准氨基酸偶联方案将其与鸟氨酸侧链偶联。用DMF彻底洗涤树脂,然后使用DMF作为转移溶剂将树脂转移回到50ml锥形管中。
将树脂脱保护,通过用5ml下述试剂(5%TIS、2%水、5%(w/v)二硫苏糖醇(DTT)、88%TFA)处理从树脂切下,允许混合3.5小时。将滤液收集到45ml冷无水乙醚中。在冷冻离心机中以3500RPM离心10分钟将沉淀物沉淀。倾析乙醚,将肽再悬浮于新鲜乙醚中。总共进行2次乙醚后处理。最后一次乙醚洗涤后,将肽空气干燥以去除残余乙醚。将肽沉淀物再悬浮于8ml乙腈(Acn)中,然后加入8ml去离子水,使其完全溶解。然后用质谱法分析肽溶液。采用电喷雾离子化进行质量分析,鉴定了含有5205.1道尔顿质量的主产物;相应于所需线性产物。粗产物(约500mg)进行了HPLC分析,其中采用250×4.6mm C18柱(Phenomenex;Torrance,CA,USA)并用2-80%乙腈(0.1%TFA)的梯度,进行30分钟。分析性HPLC鉴定了具有50%纯度的产物。然后用类似的洗脱梯度将肽在配备有C18柱的制备性HPLC上纯化。然后用HPLC和质谱法对纯化产物进行再分析:纯度96.10%和5204.6道尔顿,随后冷冻干燥。冻干后,获得6.2mg纯化产物,收率为1.2%。
基本上可根据针对实施例15的化合物合成描述的方法,通过使用PEG-马来酰亚胺作为原料替换实施例15中所用的N-丙基马来酰亚胺,合成本文所公开的PEG化GIP化合物。
本发明的其它肽可以由本领域普通技术人员使用类似于前述实施例中所公开的方法的合成方法来制备。在此示例的化合物的物理数据示于表1中。
表1
功能性测定
A.体外hGIP受体结合测定
通过如下方式制备用于体外受体结合测定的膜:在冰冷的50mMTris-HCl中用Brinkman Polytron(设定6,15秒)将表达人重组GIP受体的CHO-K1克隆细胞匀浆化,然后以39,000g进行10分钟的两次离心,其间重悬浮于新鲜缓冲液中。为了测定,在50mM Tris-HCl、0.1mg/ml杆菌肽和0.1%BSA中在25℃孵育等份试样的经洗涤的膜制品与0.05nM[125I]GIP(约2200Ci/mmol)100分钟。最终测定体积为0.5ml。通过使用Brandel多联过滤器快速滤过GF/C滤纸(预浸渍在0.5%聚乙烯亚胺中)而终止孵育。然后用5ml等份试样的冰冷缓冲液洗涤每个管和过滤器三次。特异性结合被定义为所结合的总放射性配体减去存在1000nM GIP下所结合的放射性配体。本文示例的化合物的体外hGIP受体结合数据示于表2中。
B.人和大鼠血浆半衰期测定
将GIP肽(50μL 1mg/ml)加入450μL血浆(人或大鼠)中,短暂涡旋,在37℃孵育。在不同时间如在0、1、2、3、4、8、24、32、48、56、72小时移取50μL,在微量离心管中与5μL甲酸和150μL乙腈混合,涡旋,以10K rpm离心10分钟。将上清液转移至注射小瓶中,通过LC-MS分析。LC-MS系统包括带有ESI探针的API4000质谱仪。使用正离子模式和全扫描检测。在Luna 3μC8(2)、2×30mm柱上进行HPLC分离,梯度为90%A至90%B(10分钟),流速为0.3ml/min。缓冲液A为1%在水中的甲酸,缓冲液B为1%在乙腈中的甲酸。本文示例的化合物的人和大鼠血浆半衰期数据示于表2中。
表2
与表2中所列的数据相比,在与上文所述相同的实验条件下测量了[Pro3]hGIP(1-42)-OH(PCT公布WO 00/58360中所公开的化合物)的体外hGIP受体结合数据、以及人和大鼠血浆半衰期数据,分别为170.8nM以及10.8小时和0.8小时。
C.环AMP刺激的测定
将1×105个表达人重组GIP受体的CHO-K1细胞或RIN-5F胰岛素瘤细胞接种到24孔细胞培养板(Corning Incorporate,Corning,NY,USA)中,过夜。为了测定,将细胞在500μl调节至pH 7.3的含有0.55mm IBMX(Sigma,St.Louis,MO,USA)的Hanks平衡盐溶液(Sigma,St.Louis,MO,USA)中预孵育10分钟。然后以100nM的浓度加入GIP或其类似物。在37℃孵育30分钟后,将板放置在冰上,加入500μl冰冷无水乙醇以停止反应。收集各孔的内容物,在4℃以2,700g离心20分钟以去除细胞碎片。通过放射免疫测定(New England Nuclear,Boston,MA,USA)测定上清液中的cAMP水平。
D.正常大鼠中体内胰岛素分泌的测定
体重约为275-300g的雄性Sprague Dawley大鼠用作实验对象。处理前一天,在羟基氯化物(chlorohydrate)下经颈静脉植入右心房套管。每个套管装入100u/ml肝素盐水,将其固定。大鼠禁食约18小时,然后给予本发明化合物或赋形剂(盐水/0.25%BSA)。实验那天,将等份试样的化合物融化,调至室温,充分涡旋。仔细检查自溶液产生的任何复合(compound)迹象。在化合物/葡萄糖注射前10分钟,抽取500μl血样,替换为等体积的肝素化盐水(10u/ml)。在时间0时,通过套管采集500μl血样。接着,将赋形剂或适宜剂量的化合物注射到套管中,与葡萄糖(1g/kg)或赋形剂溶液一起推入。最后,用500μl体积的肝素化盐水(10u/ml)通过套管推入剩余的葡萄糖。在葡萄糖施用后2.5、5、10和20分钟,采集另外的500μl血样;每次采集后立即通过套管静脉推注500μl肝素化盐水(10u/ml)。通过离心从血样收集血浆,在-20℃贮存直至测定胰岛素含量。总胰岛素分泌的数值总结于表3中,这些数值显示实施例105、106、118和119的化合物的体内效应。
表3
施用
本发明的肽可以以可药用盐的形式提供。此类盐的实例包括但不限于与有机酸(例如乙酸、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(pamoic acid))、无机酸(例如盐酸、硫酸或磷酸)和高分子酸(例如单宁酸、羧甲基纤维素、聚乳酸、聚乙醇酸或聚乳酸-羟基乙酸的共聚物)形成的那些盐。制备本发明肽的盐的典型方法在本领域中是熟知的,并可通过盐交换的标准方法来完成。因此,本发明肽的TFA盐(TFA盐通过使用制备性HPLC、用含有TFA的缓冲溶液洗脱而由肽的纯化中得到)可转化成另一种盐,例如,通过将肽溶解于少量0.25N乙酸水溶液中转化成乙酸盐。所得溶液上样于半制备性HPLC柱(Zorbax,300SB,C-8)。将柱子用(1)0.1N乙酸铵水溶液洗脱0.5小时,用(2)0.25N乙酸水溶液洗脱0.5小时,用(3)线性梯度(20%至100%的溶液B,历经30分钟)以4ml/min的流速洗脱(溶液A为0.25N乙酸水溶液;溶液B为0.25N在80∶20乙腈/水中的乙酸)。收集含有肽的部分,冻干。
可以改变活性成分在本发明组合物中的剂量;然而,活性成分量必要使得可以获得合适剂型。所选剂量取决于所需的疗效、施用途径和治疗的持续时间。一般而言,对于本发明活性,有效剂量的范围为1×10-7至200mg/kg/天,优选为1×10-4至100mg/kg/天,其可以单个剂量形式或分成多个剂量施用。
本发明的化合物可通过口服、胃肠外(例如肌内、腹膜内、静脉内或皮下注射或植入物)、鼻、阴道、直肠、舌下施用或局部施用途径,并且可与可药用载体一起配制以提供适于每种施用途径的剂型。
用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉末和颗粒剂。在此类固体剂型中,将活性化合物与至少一种惰性可药用载体例如蔗糖、乳糖或淀粉混合。按通常做法的那样,此类剂型也可包括除此类惰性稀释剂之外的另外的物质,例如润滑剂(如硬脂酸镁)。在胶囊、片剂和丸剂的情况下,剂型也可包括缓冲剂。此外,片剂和丸剂还可用肠溶衣制备。
用于口服施用的液体剂型包括但不限于可药用乳剂、溶液、悬液、糖浆剂、酏剂等,含有本领域常用的惰性稀释剂,例如水。除了这些惰性稀释剂之外,组合物也可包括佐剂,例如润湿剂、乳化剂和助悬剂,以及增甜剂、调味剂和芳香剂。
根据本发明用于胃肠外施用的制剂包括但不限于无菌水溶液或非水溶液、悬液、乳液等。非水溶剂或赋形剂的实例包括丙二醇、聚乙二醇、植物油,例如橄榄油和玉米油、明胶、和可注射有机酯,例如油酸乙酯。此类剂型也可包含助剂,例如防腐剂、润湿剂、乳化剂和分散剂。它们可通过例如过滤通过滞留细菌的滤器、通过将灭菌剂掺合到组合物中、通过辐射组合物或通过加热组合物而进行灭菌。它们也可制备成无菌固体组合物的形式,所述无菌固体组合物可在临用前溶解于无菌水或某些其它无菌可注射介质中。
用于直肠或阴道施用的组合物优选是栓剂,除活性物质之外,其可包含赋形剂,例如可可脂或栓剂蜡(suppository wax)。
用于鼻或舌下施用的组合物也可用本领域中众所周知的标准赋形剂来制备。
此外,本发明化合物可以以持续释放组合物(例如在下述专利和专利申请中所述的那些组合物)施用。美国专利号5,672,659记载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记载了可成凝胶的形式的含生物活性剂的持续释放组合物。美国专利号5,821,221记载了包含生物活性剂和壳聚糖的聚合物持续释放组合物。美国专利号5,916,883记载了包含生物活性剂和环糊精的持续释放组合物。PCT公布WO99/38536记载了生物活性剂的可吸收的持续释放组合物。PCT公布WO00/04916记载了在水包油工艺中制备包含治疗剂例如肽的微粒的方法。PCT公布WO00/09166记载了包含治疗剂如肽和磷酸化聚合物的复合物。PCT公布WO00/25826记载了包含治疗剂如肽和具有不可聚合内酯的聚合物的复合物。
除非以别的方式定义,本文所用的所有技术和科学术语具有本发明所属领域的普通技术人员通常理解的含义。此外,本文提及的所有出版物、专利申请、专利和其它参考文献各自完整地特此并入作为参考。
Claims (42)
1.式(I)的化合物或其可药用盐,
(R2R3)-A1-A2-A3-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:
A1是Tyr、4Hppa、或HN-CH((CH2)n-N(R4R5))-C(O);
A2是Ala、Abu、D-Abu、Acc、Aib、β-Ala、D-Ala、Gaba、Gly、Ser、D-Ser、Thr、D-Thr、Val或D-Val;
A3是Glu、Aib、Asp、NMe-Asp、Dhp、Dmt、Glu、NMe-Glu、3Hyp、4Hyp、4Ktp、Pro、hPro、Thz或Tic;
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、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、Acc或Aib;
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、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、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、Acc、Aib、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、Aib、Ala、Asp、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)烃部分,且Z0是H、OH、CO2H或CONH2;
R2、R3、R4和R5各自独立地选自由以下组成的组:H、(C1-C30)烷基、(C1-C30)杂烷基、(C1-C30)酰基、(C2-C30)链烯基、(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)链烯基、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;条件是,当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)酰基时,R3是H、(C1-C30)烷基、(C1-C30)杂烷基、(C2-C30)链烯基、(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)链烯基、取代的(C2-C30)炔基或取代的芳基(C1-C30)烷基;进一步条件是,当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)酰基时,R5是H、(C1-C30)烷基、(C1-C30)杂烷基、(C2-C30)链烯基、(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)链烯基、取代的(C2-C30)炔基或取代的芳基(C1-C30)烷基;
n每次出现时均独立地是选自包括1和5的整数1至5的整数;
s、t、x和y各自在每次出现时均独立地是选自包括1和30的整数1至30的整数;
X4、X5、X6、X7和X8各自在每次出现时均独立地是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;且
条件是当A1是4Hppa时,R2和R3缺失;
进一步条件是,该化合物的1、2和3位上仅一个氨基酸被置换或修饰;且
进一步条件是,式(I)化合物不是(D-Ala2)hGIP(1-42)、(Pro3)hGIP(1-42)(SEQ ID NO:120)、(Aib3)hGIP(1-42)(SEQ ID NO:121)、(Ser2)hGIP(1-42)(SEQ ID NO:122)、(Abu2)hGIP(1-42)(SEQ ID NO:123)、(D-Abu2)hGIP(1-42)、(D-Ser2)hGIP(1-42)、(D-Thr2)hGIP(1-42)或(D-Val2)hGIP(1-42)。
2.根据权利要求1的化合物或其可药用盐,其中:
A1是Tyr、4Hppa或Orn(N-C(O)-(CH2)12-CH3);
A2是Ala、A5c、A6c、Aib、D-Ala、Gly或Ser;
A3是Glu、Dhp、3Hyp、4Hyp、Pro、hPro或Tic;
A4是Gly或Aib;
A5是Thr、A5c或Aib;
A6是Phe或A6c;
A7是Ile、A5c、A6c或Aib;
A8是Ser或Aib;
A9是Asp或Aib;
A10是Tyr;
A11是Ser、A5c、A6c、Aib或Nle;
A12是Ile、A5c或Aib;
A13是Ala或Aib;
A14是Met、A5c、A6c或Nle;
A15是Asp;
A16是Lys;
A17是Ile或A6c;
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或A6c;
A27是Leu或A6c;
A28是Ala或Aib;
A29是Gln;
A30是Lys;
A31是Gly、Aib、Cys(Psu)、His或缺失;
A32是Lys、Cys(Psu)或缺失;
A33是Lys、Cys(Psu)或缺失;
A34是Asn、Cys(Psu)或缺失;
A35是Asp、Cys(Psu)或缺失;
A36是Trp、Cys(Psu)或缺失;
A37是Lys、Cys(Psu)或缺失;
A38是His、Cys(Psu)或缺失;
A39是Asn、Cys(Psu)或缺失;
A40是Ile、A5c、A6c、Cys(Psu)或缺失;
A41是Thr、A5c、A6c、Aib、Cys(Psu)或缺失;
A42是Gln或缺失;
A43是Cys(Psu)、Gln、His或缺失;且条件是,该化合物在位置4-43包含至少一个另外的氨基酸置换或修饰。
3.根据权利要求2的化合物,其中所述化合物是:
(Aib2,11)hGIP(1-42)-OH(SEQ ID NO:4);
(Aib2,9)hGIP(1-42)-OH(SEQ ID NO:5);
(Aib2,7)hGIP(1-42)-OH(SEQ ID NO:6);
(Aib2,5)hGIP(1-42)-OH(SEQ ID NO:7);
(Aib2,A5c5)hGIP(1-42)-OH(SEQ ID NO:8);
(Aib2,A5c7)hGIP(1-42)-OH(SEQ ID NO:9);
(Aib2,A5c12)hGIP(1-42)-OH(SEQ ID NO:10);
(Aib2,12)hGIP(1-42)-OH(SEQ ID NO:11);
(Aib2,8)hGIP(1-42)-OH(SEQ ID NO:12);
(Aib2,4)hGIP(1-42)-OH(SEQ ID NO:13);
(Aib2,A5c5)hGIP(1-30)-NH2(SEQ ID NO:14);
(Aib2,A5c7)hGIP(1-30)-NH2(SEQ ID NO:15);
(Aib2,A5c12)hGIP(1-30)-NH2(SEQ ID NO:16);
(Aib2,4)hGIP(1-30)-NH2(SEQ ID NO:17);
(Aib2,5)hGIP(1-30)-NH2(SEQ ID NO:18);
(Aib2,7)hGIP(1-30)-NH2(SEQ ID NO:19);
(Aib2,8)hGIP(1-30)-NH2(SEQ ID NO:20);
(Aib2,9)hGIP(1-30)-NH2(SEQ ID NO:21);
(Aib2,11)hGIP(1-30)-NH2(SEQ ID NO:22);
(Aib2,12)hGIP(1-30)-NH2(SEQ ID NO:23);
(Aib2,13,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:24);
(Aib2,31,A6c7)hGIP(1-42)-OH(SEQ ID NO:25);
(Aib2,41,A6c7)hGIP(1-42)-OH(SEQ ID NO:26);
(Aib2,31,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:27);
(Aib2,41,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:28);
(Aib2,A6c7,26,Nle14)hGIP(1-42)-OH(SEQ ID NO:29);
(Aib2,A6c7,27,Nle14)hGIP(1-42)-OH(SEQID NO:30);
(Aib2,A6c7,40,Nle14)hGIP(1-42)-OH(SEQ ID NO:31);
(Aib2,A6c7,41,Nle14)hGIP(1-42)-OH(SEQ ID NO:32);
(Aib2,28,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:33);
(Aib2,A6c7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:34);
(Aib2,A5c7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:35);
(Aib2,11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:36);
(A5c2,7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:37);
(Aib2,A5c7,14)hGIP(1-30)-NH2(SEQ ID NO:38);
(A6c2,7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:39);
(Aib2,A6c7,17,Nle14)hGIP(1-42)-OH(SEQ ID NO:40);
(Aib3,11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:41);
(Aib2,A6c7,14)hGIP(1-30)-NH2(SEQ ID NO:42);
(A5c2,Nle14)hGIP(1-42)-OH(SEQ ID NO:43);
(Aib2,11,A6c14)hGIP(1-42)-OH(SEQ ID NO:44);
(Aib2,A6c14)hGIP(1-42)-OH(SEQ ID NO:45);
(Aib2,A6c7)hGIP(1-42)-OH(SEQ ID NO:46);
(Aib2,A5c7,A6c14)hGIP(1-42)-OH(SEQ ID NO:47);
(Aib2,11,Nle14)hGIP(1-42)-OH(SEQ ID NO:48);
(Aib2,A5c11)hGIP(1-30)-NH2(SEQ ID NO:49);
(Aib2,13)hGIP(1-30)-NH2(SEQ ID NO:50);
(Aib2,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO :51);
(Aib2,13,Nle14)hGIP(1-30)-NH2(SEQ ID NO:52);
(Aib2,A5c11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:53);
(Aib2,A6c7,14)hGIP(1-42)-OH(SEQ ID NO:54);
(Aib2,A6c7)hGIP(1-30)-NH2(SEQ ID NO:55);
(Aib2,A5c11)hGIP(1-42)-OH(SEQ ID NO:56);
(Aib2,A5c11,Nle14)hGIP(1-42)-OH(SEQ ID NO:57);
(Aib2,A6c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:58);
(A5c2,7,A6c14)hGIP(1-42)-OH(SEQ ID NO:59);
(Aib2,13,Nle14)hGIP(1-42)-OH(SEQ ID NO:60);
(Aib2,A5c7,Nle14)hGIP(1-42)-OH(SEQ ID NO:61);
(Aib2,A5c7,14)hGIP(1-42)-OH(SEQ ID NO:62);
(Aib2,13)hGIP(1-42)-OH(SEQ ID NO:63);
(Aib2,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:64);
(Pro3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:65);
(hPro3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:66);
(Dhp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:67);
(hPro3,Aib13)hGIP(1-42)-OH(SEQ ID NO:68);
(Tic3,Aib13)hGIP(1-42)-OH(SEQ ID NO:69);
(4Hyp3,Aib13)hGIP(1-42)-OH(SEQ ID NO:70);
(4Hyp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:71);
(Tic3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:72);
(3Hyp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:73);
(Tic3,A6c14)hGIP(1-42)-OH(SEQ ID NO:74);
(hPro3,A6c14)hGIP(1-42)-OH(SEQ ID NO:75);
[Aib2,A6c7,Cys(Psu)41]hGIP(1-42)-OH(SEQ ID NO:76);
(hPro3,A5c11)hGIP(1-42)-OH(SEQ ID NO:77);
(Pro3,Aib13)hGIP(1-42)-OH(SEQ ID NO:78);
(Pro3,A5c7,14)hGIP(1-42)-OH(SEQ ID NO:79);
(Pro3,A5c11)hGIP(1-42)-OH(SEQ ID NO:80);
[Aib2,A6c7,Cys(Psu)40]hGIP(1-42)-OH(SEQ ID NO:81);
[Aib2,A6c7,Cys(Psu)39]hGIP(1-42)-OH(SEQ ID NO:82);
[Aib2,A6c7,Cys(Psu)38]hGIP(1-42)-OH(SEQ ID NO:83);
[Aib2,A6c7,Cys(Psu)36]hGIP(1-42)-OH(SEQ ID NO:84);
(Tic3,A5c11)hGIP(1-42)-OH(SEQ ID NO:85);
(hPro3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:86);
(4Hyp3,A6c14)hGIP(1-42)-OH(SEQ ID NO:87);
[Aib2,A6c7,Cys(Psu)35]hGIP(1-42)-OH(SEQ ID NO:88);
[Aib2,A6c7,Cys(Psu)34]hGIP(1-42)-OH(SEQ ID NO:89);
(4Hyp3,A5c11)hGIP(1-42)-OH(SEQ ID NO:90);
(4Hyp3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:91);
(Tic3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:92);
[Aib2,A6c7,Cys(Psu)31]hGIP(1-42)-OH(SEQ ID NO:93);
(Pro3,A6c14)hGIP(1-42)-OH(SEQID NO:94);
(Pro3,A5c11,Nle14)hGIP(1-30)-OH(SEQ ID NO:95);
(Aib2,A6c7,Gln43)hGIP(1-43)-OH(SEQ ID NO:96);
[Aib2,A6c7,Cys(Psu)32]hGIP(1-42)-OH(SEQ ID NO:97);
[Aib2,A6c7,Cys(Psu)43]hGIP(1-43)-OH(SEQ ID NO:98);
(Pro3,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:99);
(Pro3,A6c7)hGIP(1-30)-NH2(SEQ ID NO:100);
(Pro3,A5c11)hGIP(1-30)-NH2(SEQ ID NO:101);
[Aib2,A6c7,Cys(Psu)33]hGIP(1-42)-OH(SEQ ID NO:102);
[Aib2,A6c7,Cys(Psu)37]hGIP(1-42)-OH(SEQ ID NO:103);
(4Hppa1,Aib13)hGIP(1-42)-OH(SEQ ID NO:104);
(Pro3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:105);
[Orn1(N-C(O)-(CH2)12-CH3),A6c7]hGIP(1-42)-OH(SEQ ID NO:106);
(D-Ala2,A5c11,40)hGIP(1-42)-OH;
(D-Ala2,A5c11,His43)hGIP(1-43)-OH;
(D-Ala2,A5c11,41)hGIP(1-42)-OH;
(D-Ala2,A6c11,14,41)hGIP(1-42)-OH;
(Gly2,A6c11,14,41)hGIP(1-42)-OH(SEQ ID NO:113);
(Gly2,Aib13,A5c40)hGIP(1-42)-OH(SEQ ID NO:114);
(Gly2,A5c11,41)hGIP(1-42)-OH(SEQ ID NO:115);
(Gly2,A5c11,His43)hGIP(1-43)-OH(SEQ ID NO:116);
(Gly2,A5c11,Nle14,His43)hGIP(1-43)-OH(SEQ ID NO:117);
(D-Ala2,A5c11,Nle14,His43)hGIP(1-43)-OH;
(D-Ala2,A5c11,14,His43)hGIP(1-43)-OH;
(D-Ala2,A5c11,14)hGIP(1-30)-NH2;
(D-Ala2,A5c11,His31)hGIP(1-31)-NH2;或
(Aib2,A5c11,14,His43)hGIP(1-43)-OH(SEQ ID NO:118)。
4.根据权利要求2的化合物或可药用盐,其中A2是D-Ala。
5.根据权利要求4的化合物或其可药用盐,其中所述化合物是:
(D-Ala2,A5c11,40)hGIP(1-42)-OH;
(D-Ala2,A5c11,His43)hGIP(1-43)-OH;
(D-Ala2,A5c11,41)hGIP(1-42)-OH;
(D-Ala2,A6c11,14,41)hGIP(1-42)-OH;
(D-Ala2,A5c11,Nle14,His43)hGIP(1-43)-OH;
(D-Ala2,A5c11,14,His43)hGIP(1-43)-OH;
(D-Ala2,A5c11,14)hGIP(1-30)-NH2;或
(D-Ala2,A5c11,His31)hGIP(1-31)-NH2。
6.根据权利要求2的化合物或其可药用盐,其中A31至A43缺失。
7.根据权利要求6的化合物或其可药用盐,其中所述化合物是:
(Aib2,A5c5)hGIP(1-30)-NH2(SEQ ID NO:14);
(Aib2,A5c7)hGIP(1-30)-NH2(SEQ ID NO:15);
(Aib2,A5c12)hGIP(1-30)-NH2(SEQ ID NO:16);
(Aib2,4)hGIP(1-30)-NH2(SEQ ID NO:17);
(Aib2,5)hGIP(1-30)-NH2(SEQ ID NO:18);
(Aib2,7)hGIP(1-30)-NH2(SEQ ID NO:19);
(Aib2,8)hGIP(1-30)-NH2(SEQ ID NO:20);
(Aib2,9)hGIP(1-30)-NH2(SEQ ID NO:21);
(Aib2,11)hGIP(1-30)-NH2(SEQ ID NO:22);
(Aib2,12)hGIP(1-30)-NH2(SEQ ID NO:23);
(Aib2,A6c7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:34);
(Aib2,A5c7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:35);
(Aib2,11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:36);
(A5c2,7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:37);
(Aib2,A5c7,14)hGIP(1-30)-NH2(SEQ ID NO:38);
(A6c2,7,Nle14)hGIP(1-30)-NH2(SEQ ID NO:39);
(Aib2,11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:41);
(Aib2,A6c7,14)hGIP(1-30)-NH2(SEQ ID NO:42);
(Aib2,A5c11)hGIP(1-30)-NH2(SEQ ID NO:49);
(Aib2,13)hGIP(1-30)-NH2(SEQ ID NO:50);
(Aib2,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:51);
(Aib2,13,Nle14)hGIP(1-30)-NH2(SEQ ID NO:52);
(Aib2,A5c11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:53);
(Aib2,A6c7)hGIP(1-30)-NH2(SEQ ID NO:55);
(Pro3,A5c11,Nle14)hGIP(1-30)-OH(SEQ ID NO:95);
(Pro3,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:99);
(Pro3,A6c7)hGIP(1-30)-NH2(SEQ ID NO:100);
(Pro3,A5c11)hGIP(1-30)-NH2(SEQ ID NO:101);
(D-Ala2,A5c11,14)hGIP(1-30)-NH2(SEQ ID NO:121)。
8.主要由天然hGIP氨基酸序列N端的前30个连续氨基酸残基的序列组成的化合物或其可药用盐,其中该序列包括在2位上的A5c、A6c、Aib、D-Ala、Gly或Ser置换,以及在位置3-30上的至少一个另外的氨基酸置换或修饰。
9.根据权利要求8的化合物或其可药用盐,其中:A2是Aib;A3是Pro;且A7、A11、A13和A14中的至少一个不是天然GIP中相应位置的氨基酸残基。
10.根据权利要求9的化合物或其可药用盐,其中所述化合物是:
(Aib2,13,Pro3,Nle14)hGIP(1-30)-NH2(SEQ ID NO:107);
(Aib2,Pro3,A6c7)hGIP(1-30)-NH2(SEQ ID NO:108);
(Aib2,Pro3,A5c11)hGIP(1-30)-NH2(SEQ ID NO:109);
(Aib2,Pro3,A5c11,Nle14)hGIP(1-30)-NH2(SEQ ID NO:110);或
(Aib2,Pro3,A5c11,A6c14)hGIP(1-30)-NH2(SEQ ID NO:111)。
11.包括在位置2上的A5c、A6c、Aib、D-Ala、Gly或Ser置换以及在位置1和3-42上的至少一个另外的氨基酸置换或修饰的GIP类似物或其可药用盐。
12.根据权利要求11的化合物或其可药用盐,其中该序列包含在位置2上的Aib置换。
13.根据权利要求12的化合物或其可药用盐,其中所述化合物是:
(NMe-Tyr1,Aib2,A5c11,Nle14)hGIP(1-42)-OH(SEQ ID NO:112)。
14.根据权利要求2的化合物或其可药用盐,其中:A2是Ala、A5c、A6c或Gly;且A3是Glu、Dhp、3Hyp、4Hyp、hPro或Tic。
15.根据权利要求14的化合物或其可药用盐,其中所述化合物是:
(hPro3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:66);
(Dhp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:67);
(hPro3,Aib13)hGIP(1-42)-OH(SEQ ID NO:68);
(Tic3,Aib13)hGIP(1-42)-OH(SEQ ID NO:69);
(4Hyp3,Aib13)hGIP(1-42)-OH(SEQ ID NO:70);
(4Hyp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:71);
(Tic3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:72);
(3Hyp3,Aib13,Nle14)hGIP(1-42)-OH(SEQ ID NO:73);
(Tic3,A6c14)hGIP(1-42)-OH(SEQ ID NO:74);
(hPro3,A6c14)hGIP(1-42)-OH(SEQ ID NO:75);
(hPro3,A5c11)hGIP(1-42)-OH(SEQ ID NO:77);
(Tic3,A5c11)hGIP(1-42)-OH(SEQ ID NO:85);
(hPro3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:86);
(4Hyp3,A6c14)hGIP(1-42)-OH(SEQ ID NO:87);
(4Hyp3,A5c11)hGIP(1-42)-OH(SEQ ID NO:90);
(4Hyp3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:91);
(Tic3,A5c11,A6c14)hGIP(1-42)-OH(SEQ ID NO:92);
(4Hppa1,Aib13)hGIP(1-42)-OH(SEQ ID NO:104);
[Orn1(N-C(O)-(CH2)12-CH3),A6c7]hGIP(1-42)-OH(SEQ ID NO:106);
(Gly2,A6c11,14,41)hGIP(1-42)-OH(SEQ ID NO:113);
(Gly2,Aib13,A5c40)hGIP(1-42)-OH(SEQ ID NO:114);
(Gly2,A5c11,41)hGIP(1-42)-OH(SEQ ID NO:115);
(Gly2,A5c11,His43)hGIP(1-43)-OH(SEQ ID NO:116);或
(Gly2,A5c11,Nle14,His43)hGIP(1-43)-OH(SEQ ID NO:117)。
16.根据权利要求1-15中任一项的化合物或其可药用盐,还包含共价连接的PEG部分。
17.根据权利要求16的化合物或其可药用盐,其中所述PEG通过Cys(马来酰亚胺)、hCys(马来酰亚胺)或Pen(马来酰亚胺)连接体与该化合物连接,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)。
18.根据权利要求17的化合物或其可药用盐,其中PEG化在氨基酸残基位置16、30和31-43中的任何一个上发生,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)被放入氨基酸残基位置16、30和31-43之任何一个中。
19.根据权利要求18的化合物或其可药用盐,其中PEG化在氨基酸残基位置32、33和43中的任何一个上发生,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)被放入氨基酸残基位置32、33和43之任何一个中。
20.根据权利要求19的化合物或其可药用盐,其中所述PEG部分具有约2,000至约80,000的平均分子量。
21.根据权利要求20的化合物或其可药用盐,其中所述PEG选自由以下组成的组: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-10K PEG)、Cys(琥珀酰亚胺-N-20K PEG)、Cys(琥珀酰亚胺-N-30KPEG)、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-50KPEG)、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-50KPEG)或Pen(琥珀酰亚胺-N-60K PEG)。
22.根据权利要求17-21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是直链。
23.根据权利要求22的化合物或其可药用盐,其中所述直链琥珀酰亚胺-N-PEG是琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-PEG。
24.根据权利要求17-21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是支链。
25.根据权利要求24的化合物或其可药用盐,其中所述支链琥珀酰亚胺-N-PEG是琥珀酰亚胺-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(PEG)-CH2-PEG。
26.药物组合物,其包含有效量的权利要求1-25中任一项的肽类似物。
27.权利要求26的药物组合物,其还包含可药用载体。
28.在有需要的受试者中自GIP受体引发激动剂效应的方法,所述方法包括对所述受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物。
29.在有需要的受试者中自GIP受体引发拮抗剂效应的方法,所述方法包括对所述受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物。
30.用于治疗由GIP-受体结合介导的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物的步骤。
31.权利要求30的方法,其中所述由GIP-受体结合介导的病症或疾病选自由以下组成的组:1型糖尿病、2型糖尿病、肥胖症、胰岛素抗性、葡萄糖耐性、脂肪肝、胰高血糖素瘤、气道分泌性病症、代谢紊乱、关节炎、骨质疏松症、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、肾病综合征、肝硬化、肺水肿、高血压和其中希望食物摄入减少和/或体重减轻的病症。
32.治疗糖尿病的方法,其包括向有需要的受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物的步骤。
33.权利要求32的方法,其中所述糖尿病是2型糖尿病。
34.治疗糖尿病相关病症的方法,其包括向有需要的受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物的步骤。
35.权利要求34的方法,其中所述糖尿病相关病症选自由以下组成的组:高血糖症、高胰岛素血症、葡萄糖耐性受损、空腹葡萄糖受损、血脂异常、高甘油三酯血症和胰岛素抗性。
36.用于治疗或预防继发性糖尿病病因的方法,其包括向有需要的受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物的步骤。
37.权利要求36的方法,其中所述继发性病因选自由以下组成的组:糖皮质激素过量、生长激素过量、嗜铬细胞瘤和药物引起的糖尿病。
38.治疗肥胖症的方法,其包括向有需要的受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物的步骤。
39.在有需要的受试者中刺激胰岛素分泌的方法,包括向所述受试者施用治疗有效量的权利要求1-25中任一项的肽类似物或权利要求26或权利要求27的药物组合物,。
40.权利要求1-25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与受损的GIP-受体类似物结合有关的疾病或病症的药物中的用途。
41.根据权利要求40的用途,用于制备预防或治疗胰腺β细胞凋亡的药物。
42.根据权利要求40的用途,用于制备加强胰腺β细胞的葡萄糖依赖性增殖的药物。
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- 2009-08-07 CN CN201510177971.8A patent/CN104829706A/zh active Pending
- 2009-08-07 JP JP2011522070A patent/JP2011530508A/ja active Pending
- 2009-08-07 WO PCT/US2009/004552 patent/WO2010016940A2/en active Application Filing
- 2009-08-07 US US13/057,760 patent/US9074014B2/en not_active Expired - Fee Related
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104470948A (zh) * | 2012-05-03 | 2015-03-25 | 西兰制药公司 | Gip-glp-1双激动剂化合物及方法 |
CN104470948B (zh) * | 2012-05-03 | 2018-06-15 | 西兰制药公司 | Gip-glp-1双激动剂化合物及方法 |
TWI689515B (zh) * | 2012-05-03 | 2020-04-01 | 丹麥商西蘭製藥公司 | Gip-glp-1雙重促效劑化合物及方法 |
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EP2987805A3 (en) | 2016-04-13 |
MX2011001031A (es) | 2011-04-26 |
AU2009280017A1 (en) | 2010-02-11 |
AU2009280017B2 (en) | 2013-01-10 |
CN104829706A (zh) | 2015-08-12 |
EP2328922A2 (en) | 2011-06-08 |
CN102171244B (zh) | 2015-05-13 |
EA020019B1 (ru) | 2014-08-29 |
US9074014B2 (en) | 2015-07-07 |
JP2011530508A (ja) | 2011-12-22 |
WO2010016940A2 (en) | 2010-02-11 |
BRPI0916890A2 (pt) | 2019-09-24 |
WO2010016940A3 (en) | 2010-04-15 |
US20150252092A1 (en) | 2015-09-10 |
CA2732949A1 (en) | 2010-02-11 |
KR101417873B1 (ko) | 2014-07-09 |
EP2987805A2 (en) | 2016-02-24 |
US20110136733A1 (en) | 2011-06-09 |
JP2014028846A (ja) | 2014-02-13 |
EA201170304A1 (ru) | 2011-10-31 |
KR20130093692A (ko) | 2013-08-22 |
CA2732949C (en) | 2016-12-20 |
EP2328922A4 (en) | 2013-01-02 |
KR20110043686A (ko) | 2011-04-27 |
JP5865324B2 (ja) | 2016-02-17 |
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