CN101282738B - 生长素释放肽类似物 - Google Patents
生长素释放肽类似物 Download PDFInfo
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- CN101282738B CN101282738B CN200680035324.2A CN200680035324A CN101282738B CN 101282738 B CN101282738 B CN 101282738B CN 200680035324 A CN200680035324 A CN 200680035324A CN 101282738 B CN101282738 B CN 101282738B
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- ghrelin
- glu
- hexyl
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Classifications
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明包含如下所述的根据式(I)或(II)的肽基类似物和其可药用盐:(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-R1其中对于式(I)和(II)中每一个的A1至A28和R1至R3的定义在说明书中提供,和包含有效量的具有激动剂或拮抗剂生长素释放肽活性的式(I)化合物的药物组合物及其治疗和非治疗用途。
Description
发明领域
本发明涉及具有激动剂或拮抗剂生长素释放肽活性的肽基类似物及其治疗用途。
现有技术描述
生长素释放肽是最近发现的促进食欲的激素,其作为前激素原产生,该前激素原被蛋白水解加工得到下列序列的肽:H-Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg-NH2(Kojima,M.等,Nature,(1999),402(6762):656-60)。生长素释放肽由衬于胃底的上皮细胞产生,并且作用为刺激食欲;在进餐前其水平增加,之后又降低。
已知来自数种哺乳动物和非哺乳动物物种的生长素释放肽的天然结构(Kaiya,H.等,J.Biol.Chem.,(2001),276(44):40441-8;以及国际专利申请PCT/JP00/04907[WO 01/07475])。生长素释放肽中存在的核心区负责在GHS受体处的活性,其包含4个N-末端氨基酸,其中第3位的丝氨酸通常被正辛酸修饰。天然生长素释放肽除了被正辛酸酰化外,也可以被正癸酸酰化(Kaiya,H.等,J.Biol.Chem.,(2001),276(44):40441-8)。
肥胖个体中血浆生长素释放肽水平低于瘦弱个体的水平,并且在更瘦的个体中生长素释放肽水平在午夜至日出的时间内升高,这表明在肥胖个体的循环***中有缺点(Yildiz,B.O.等,Proc.Natl.Acad.Sci.USA,(2004),101(28):10434-9)。已经发现,患有进食障碍神经性厌食的个体和具有癌症诱导的恶病质的患者具有较高血浆水平的生长素释放肽(Garcia,J.M.等,J.Clin.Endocrin.Metab.,(2005),90(5):2920-6)。
在动物和人中,生长素释放肽通过其与GH促分泌素(GHS)受体(GHS-R)的相互作用强力刺激前叶垂体分泌生长激素(GH),主要在下丘脑水平(Ukkola,O.等,Ann.Med.,(2002),34(2):102-8;和Kojima,M.等,Nature,(1999),402(6762):656-60)。生长素释放肽的GH释放活性通过在垂体水平和主要在下丘脑水平活化GHS受体介导(Kojima,M.等,Nature,(1999),402(6762):656-60)。
在发现生长素释放肽是GHS受体的天然配体之前,已经知道GH从垂体生长激素细胞的脉冲式释放被两种下丘脑神经肽调节:GH释放激素(GHRH)和促生长素抑制素。GHRH刺激GH释放,而促生长素抑制素抑制GH分泌(Frohman,L.A.等,Endocr.Rev.,(1986),7(3):223-53;和Strobl,J.S.等,Pharmacology Review(1994)46:1-34)。生长素释放肽可能增强GHRH分泌神经元的活性,而同时又作为功能性促生长素抑制素拮抗剂(Ghigo,E.等,Eur.J Endocri.,(1997),136(5):445-60)。
GH从垂体生长激素细胞的释放还可以被GH释放肽(GHRP)控制。发现在包括人在内的数个物种中,六肽His-D-Trp-Ala-Trp-D-Phe-Lys-酰胺(GHRP-6)以剂量依赖性方式从生长激素细胞释放GH(Bowers,C.Y.等,Endocrinology,(1984),114(5):1537-45)。后来对GHRP-6的化学研究导致鉴定出其它有效的合成性GH促分泌剂,如GHRP-I、GHRP-2和海沙瑞林(Cheng,K.等,Endocrinology,(1989),124(6):2791-8;Bowers,C.Y.,NovelGH-Releasing Peptides,Molecular and Clinical Advances in PituitaryDisorders,Ed:Melmed,S.,Endocrine Research and Education,Inc.,LosAngeles,CA,USA,(1993),153-7;和Deghenghi,R.等,Life Sci.,(1994),54(18):1321-8)。这三种化合物的结构是:
GHRP-IAla-His-D-(2′)-Nal-Ala-Trp-D-Phe-Lys-NH2;
GHRP-2D-Ala-D-(2′)-Nal-Ala-Trp-D-Nal-Lys-NH2;和
海沙瑞林His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2。
GHS可以以与GHRH不同的机理刺激GH分泌(Bowers,C.Y.等,Endocrinology,(1984),114(5):1537-45;Cheng,K.等,Endocrinology, (1989),124(6):2791-8;Bowers,C.Y.,Novel GH-Releasing Peptides,Molecular and Clinical Advances in Pituitary Disorders,Ed:Melmed,S.,Endocrine Research and Education,Inc.,Los Angeles,CA,USA,(1993),153-7;和Deghenghi,R.等,Life Sci.,(1994),54(18):1321-8)。
肽基GHS的低口服生物利用度(<1%)催促研究在垂体中模拟GHRP-6作用的非肽化合物。已经报道数种苯并内酰胺和螺1,2二氢化茚在包括人在内的数个动物物种中刺激GH释放(Smith,R.G.等,Science,(1993),260(5114):1640-3;Patchett,A.A.等,Proc.Natl.Acad.Sci.USA,(1995),92(15):7001-5;Chen,M.-H.等,Bioorg.Mod.Chem.Letts.,(1996),6(18):2163-8)。小螺1,2二氢化茚的具体实例是MK-0677(Patchett,A.A.等,Proc.Natl.Acad.Sci.USA,(1995),92(15):7001-5):
GHS的作用(肽和非肽)通过特异受体介导(Howard,A.D.等,Science,(1996),273(5277):974-7;和Pong,S.S.等,Mol.Endocri.,(1996),10(1):57-61)。该受体存在于多个哺乳动物物种的垂体和下丘脑中(GHSR1a),并且与GH释放激素受体不同。GHS受体还可以在中枢神经***和外周组织的其它区域检测到,例如肾上腺、甲状腺、心脏、肺、肾脏和肌肉(Chen,M.-H.等,Bioorg.Med.Chem.Letts.,(1996),6(18):2163-9;Howard,A.D.等,Science,(1996),273(5277):974-7;Pong,S.S.等,Mol.Endocri.,(1996),10(1):57-61;Guan,X.-M.等,Mol.Brain Res.,(1997),48(1):23-9;和McKee,K.K.等,Genomics,(1997),46(3):426-34)。截短形式的GHSR1a已有报道(Howard,A.D.等,Science,(1996),273(5277):974-7)。
GHS受体是G蛋白偶联受体。GHS受体活化的作用包括钾通道的去极化和抑制、细胞内肌醇三磷酸(IP3)浓度的增加以及细胞内钙浓度的瞬间 升高(Pong,S.S.等,Mol.Endocri.,(1996),10(1):57-61;Guan,X.-M.等,Mol.Brain Res.,(1997),48(1):23-9;和McKee,K.K.等,Genomics,(1997),46(3):426-34)。
GHS分子如生长素释放肽和其类似物具有多种不同的治疗用途(美国专利号6,566,337;Inui,A.,FASEB J.,(2004),18(3):439-56;Muller,E.E.等,Neurobiol.Aging,(2002),23(5):907-19;Casanueva,F.F.等,TrendsEndocrinol.Metab.,(1999),10(1):30-8;和Ankerson,M.等,DrugDiscovery Today,(1999),4:497-506)和诊断用途。在GHS受体具有激动剂作用的化合物显示改善GH缺乏状态(美国专利号6,861,409和6,967,237;以及Casanueva,F.F.等,Trends Endocrinol.Metab,(1999),10(1):30-8)、增加肌肉质量(美国专利号6,861,409和6,967,237)和/或体力(Ankerson,M.等,Drug Discovery Today,(1999),4:497-506)、提高骨密度(美国专利号6,861,409、6,967,237和6,251,902;以及Sibilia,V.等,Growth Horm.IGFRes.,(1999),9(4):219-27)、治疗骨质疏松症(国际专利申请号PCT/IB96/01353[WO 97/24369]和PCT/IB98/00873[WO 98/58947];以及Casanueva,F.F.等,Trends Endocrinol.Metab.,(1999),10(1):30-8)、克服性功能障碍(美国专利号6,967,237;以及Casanueva,F.F.等,TrendsEndocrinol.Metab.,(1999)10(1):30-8)、治疗心血管病(国际专利申请号PCT/IB96/01353[WO 97/24369]和PCT/IB98/00873[WO 98/58947];美国专利号6,251,902;De Gennaro Colonna,V.等,Eur.J.Pharmacol.,(1997),334(2-3):201-7;以及Casanueva,F.F.等,Trends Endocrinol.Metab.,(1999),10(1):30-8)、缓解关节炎疼痛(Granado,M.,Am.J.Endo.Metab.,(2005),288:486-92)、预防或减轻阿尔茨海默病发作(美国专利号6,686,359和6,566,337)和/或治疗***性红斑狼疮或炎性肠病,例如克隆病或溃疡性结肠炎(美国专利公布号2002/0013320)。
生长素释放肽的激动剂类似物可以促进增加体重(美国专利号6,967,237;Tschop,M.等,Nature,(2000),407(6806):908-13;以及Tschop,M.等,Endocrinology,(2002),143(2):558-68),这反过来可用于维持预期 体重(美国专利号6,861,409和6,967,237)和/或恢复身体功能(美国专利号6,967,237和6,251,902;以及国际专利申请号PCT/IB96/01353[WO97/24369])。
生长素释放肽还增加食欲(美国专利号6,967,237;以及Okada,K.等,Endocrinology,(1996),137(11):5155-8)。照此,生长素释放肽常用于治疗患有某些疾病或障碍或者接受医学疗法的患者,这些患者通常伴有不良体重减轻,例如厌食症(美国专利号6,967,237;以及Tschop,M.等,Endocrinology,(2002),143(2):558-68)、贪食症(美国专利号6,967,237)、恶病质(美国专利号6,967,237和6,251,902),特别是癌症诱导的恶病质(美国专利号6,967,237;国际专利申请号PCT/DK2004/000529[WO 05/014032];和Tschop,M.等,Endocrinology,(2002),143:558-68),艾滋病(美国专利号6,861,409和6,967,237;以及Tschop,M.等,Endocrinology,(2002),143(2):558-68)、体弱和/或老年人中的消瘦综合征(美国专利号6,861,409和6,967,237;国际专利申请号PCT/IB96/01353[WO 97/24369];以及Ankerson,M.等,Drug Discovery Today,(1999)4:497-506)以及慢性肾脏功能衰竭(Casanueva,F.F.等,Trends Endocri.Metab.,(1999),10(1):30-8)。对传统上伴有体重减轻的医学治疗包括化学疗法、放射疗法、暂时或永久固定和/透析(美国专利号6,967,237和6,251,902)。
肥胖是糖尿病的主要危险因素并且大部分非胰岛素依赖型糖尿病(称作“NIDDM”)患者是肥胖的。该两种疾病的特征在于提高的循环胰岛素水平和降低的GH水平。对GH缺乏成人(Jorgensen,J.O.等,Lancet,(1989),1(8649):1221-5)、肥胖女性(Richelsen,B.等,Am.J.Physiol.,(1994),266(2Pt 1):E211-6)和老年男性(Rudman,D.等,Horm.Res.,(1991),36(Suppl1):73-81)的GH治疗表明引起瘦体重、肝质量和肌肉质量增加,而脂肪质量降低。因此,施用生长素释放肽激动剂对于除GH致糖尿病作用之外的肥胖而言是一种有吸引力的疗法(美国专利号6,251,902;Ankerson,M.等,Drug Discovery Today,(1999)4:497-506;以及Casanueva,F.F.等,TrendsEndocri.Metab.,(1999),10(1):30-8)。同样,糖尿病并发症如视网膜病变和/ 或治疗心血管疾病(美国专利号6,967,237;以及美国专利申请公布号2003/0211967)可以通过生长素释放肽间接治疗。
自相矛盾的是,生长素释放肽拮抗剂可以用于在肥胖个体(其中所述的肥胖不是因为NIDDM的发作)中(美国专利号6,967,237;以及美国专利申请公布号2003/0211967)以及数种其它经鉴定的适应症中促进体重减轻。在GHS受体处具有拮抗剂作用以促进GH分泌抑制的化合物,例如生长素释放肽拮抗剂类似物,表明逆转过度的GH分泌(美国专利申请公布号2002/0187938)、在非肥胖中促进体重减轻(美国专利号6,967,237)、维持理想体重和/或降低食欲(美国专利号6,967,237)。过量的体重是诸多疾病或状况的促成因素,所述疾病或状况如高血压、血脂异常和心血管病(美国专利申请公布号2003/0211967;以及美国专利号6,967,237)以及胆结石、骨关节炎(美国专利号6,967,237)、某些癌症(美国专利申请公布号2003/0211967和2004/0157227;以及美国专利号6,967,237)和普-威综合征(美国专利号6,950,707;国际专利申请号PCT/US2004/008385[WO 04/084943];Haqq,A.M.等,J.Clin.Endocri.Metab.,(2003),88(1):174-8;以及Cummings,D.E.等,Nat.Med.,(2002),8(7):643-4)。促进体重减轻的生长素释放肽拮抗剂因此降低了此类疾病或状况的可能性和/或包含对于此类疾病或状况的至少部分治疗。还公开了GHS分子拮抗剂能够结合至肿瘤组织,从而导致降低靶组织例如肺肿瘤、乳腺肿瘤、甲状腺肿瘤或胰腺肿瘤中的肿瘤细胞的数量(国际专利申请号PCT/EP99/08662[WO 00/29011])。
还可以采用GH促分泌素类似物促进胃肠运动,特别是患有源自术后肠梗阻或糖尿病或慢性糖尿病状态发作偶发胃肌轻瘫的胃肠运动降低的患者(美国专利号6,548,501)。
此外,生长素释放肽在治疗哺乳动物受试者炎症是有效的(国际专利申请号PCT/US2005/016565[WO 2005/110463])。特别地,炎症可以与病毒、细菌、寄生虫或真菌感染有关。可用生长素释放肽治疗的病毒感染包括单纯疱疹病毒1型、单纯疱疹病毒2型、巨细胞病毒、EB病毒、水痘-带状疱疹病毒、人疱疹病毒6、人疱疹病毒7、人疱疹病毒8、天花病毒、水疱 性口炎病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒、鼻病毒、冠状病毒、甲型流感病毒、乙型流感病毒、麻疹病毒、多瘤病毒、人***瘤病毒、呼吸道合胞病毒、腺病毒、柯萨奇病毒、登革热病毒、腮腺炎病毒、脊髓灰质炎病毒、狂犬病病毒、劳斯肉瘤病毒、黄热病毒、埃波拉病毒、马尔堡病毒、拉沙热病毒、东方马脑炎病毒、日本脑炎病毒、圣路易斯脑炎病毒、墨累山谷热病毒、西尼罗病毒、立夫特山谷热病毒、轮状病毒A、轮状病毒B、轮状病毒C、Sindbis病毒、猿猴免疫缺陷病毒、人T细胞白血病病毒1型、汉坦病毒、风疹病毒、猿猴免疫缺陷病毒、人免疫缺陷病毒1型和人免疫缺陷病毒2型(国际专利申请号PCT/US2005/016565[WO 2005/110463])。
可以用生长素释放肽治疗的导致炎症的细菌感染(国际专利申请号PCT/US2005/016565[WO 2005/110463])包括结核分枝杆菌(M.tuberculosis)、牛分枝杆菌(M bovis)、牛分枝杆菌BCG株、BCG亚株、鸟分枝杆菌(M.avium)、胞内分枝杆菌(M intracellulare)、非洲分枝杆菌(Mafricanum)、堪萨斯分枝杆菌(M kansasii)、海分枝杆菌(M marinum)、溃疡分支杆菌(M ulcerans)、鸟分支杆菌副结核亚型(M.avium subspeciesparatuberculosis)、星形诺卡氏菌(Nocardia asteroides)、其它诺卡氏菌物种、嗜肺军团菌(Legionella pneumophila)、其它军团菌物种、伤寒沙门氏菌(Salmonella typhi)、其它其它沙门氏菌物种、志贺氏菌(Shigella)、鼠疫耶尔森氏菌(Yersinia pestis)、溶血巴斯德菌(Pasteurella haemolytica)、多杀巴斯德菌(Pasteurella multocida)、其它巴斯德菌物种、胸膜炎肺炎放线杆菌(Actinobacillus pleuropneumoniae)、单核细胞增生利斯特氏菌(Listeriamonocytogenes)、绵羊利斯特氏菌(Listeria ivanovii)、流产布鲁氏菌(Brucellaabortus)、其它布鲁氏菌物种、反刍类考德里氏体(Cowdria ruminantium)、肺炎衣原体(Chlamydia pneumoniae)、沙眼衣原体(Chlamydia trachomatis)、鹦鹉衣原体(Chlamydia psittaci)、贝纳柯克斯体(Coxiella burnetti)、其它立克次体物种、埃里希氏体(Ehrlichia)物种、金黄色葡萄球菌(Staphylococcusaureus)、表皮葡萄球菌(Staphylococcus epidermidis)、酿脓链球菌 (Streptococcus pyogenes)、无乳链球菌(Streptococcus agalactiae)、炭疽芽孢杆菌(Bacillus anthracis)、大肠杆菌(Escherichia coli)、霍乱弧菌(Vibriocholerae)、弯曲杆菌(Campylobacter)物种、脑膜炎奈瑟氏菌(Neiserriameningitidis)、淋病奈瑟氏菌(Neiserria gonorrhea)、铜绿假单胞菌(Pseudomonas aeruginosa)、其它假单胞菌物种、流感嗜血菌(Haemophilusinfluenzae)、杜克雷嗜血杆菌(Haemophilus ducreyi)、其它嗜血菌物种、破伤风梭菌(Clostridium tetani)、其它梭菌物种、小肠结肠炎耶尔森氏菌(Yersinia enterolitica)和其它耶尔森氏菌物种(国际专利申请号PCT/US2005/016565[WO 2005/110463])。
用生长素释放肽可以治疗的炎症(国际专利申请号PCT/US2005/016565[WO 2005/110463])还可以是由寄生虫或真菌引起的,所述寄生虫包括鼠弓形虫(Toxoplasma gondii)、疟原虫属(Plasmodium)、布鲁斯锥虫(Trypanosoma brucei)、克鲁斯锥虫(Trypanosoma cruzi)、利什曼原虫属(Leishmania)、血吸虫属(Schistosoma)和溶组织内阿米巴(Entamoebahistolytica),所述真菌例如白色念珠菌(Candida albicans)、新型隐球菌(Cryptococcus neoformans)、荚膜组织胞浆菌(Histoplama capsulatum)、烟曲霉(Aspergillus fumigatus)、粗球类芽生菌(Coccidiodes immitis)、巴西副球孢子菌(Paracoccidiodes brasiliensis)、皮炎芽生菌(Blastomycesdermitidis)、卡氏肺孢菌(Pneomocystis carnii)、马尔尼菲青霉(Penicilliummarneffi)和细链格孢(Alternaria alternate)(国际专利申请号PCT/US2005/016565[WO 2005/110463])。
由肝脏毒性或抑制排斥导致的炎症也可以通过生长素释放肽治疗(国际专利申请号PCT/US2005/016565[WO 2005/110463])。肝脏毒性可以与癌症治疗有关。在一些情况下,癌症治疗,例如化学疗法可以引起肝脏毒性。由化学疗法的细胞凋亡引起的肝脏毒性可以通过施用生长素释放肽、生长素释放肽激动剂或生长素释放肽拮抗剂治疗(国际专利申请号PCT/US2005/016565[WO 2005/110463])。
与癌症有关的炎症也可以用生长素释放肽治疗(国际专利申请号 PCT/US2005/016565[WO 2005/110463])。此类癌症包括淋巴瘤、白血病、蕈样肉芽肿、癌、腺癌、肉瘤、神经胶质瘤、胚细胞瘤、成神经细胞瘤、浆细胞瘤、组织细胞瘤、黑素瘤、腺瘤、乏氧肿瘤、骨髓瘤、艾滋病相关淋巴瘤或艾滋病相关肉瘤、转移癌、膀胱癌、脑癌、神经***癌症、成胶质细胞瘤、卵巢癌(国际专利申请号PCT/AU02/00582[WO 02/090387];以及Gaytan,F.等,J.Clin.Endocri.Metab.,(2005),90(3):1798-804)、皮肤癌、肝癌、口腔、咽、喉、和肺的鳞状细胞癌、结肠癌、***(国际专利申请号PCT/AU02/00582[WO 02/090387])、乳腺癌(国际专利申请号PCT/AU02/00582[WO 02/090387];以及Cassoni,P.等,J.Clin.Endocri.Metab.,(2001),86(4):1738-45)、上皮癌、肾癌(Jungwirth,A.等,Proc.Natl.Acad.Sci.USA,(1997),94(11):5810-3)、泌尿生殖器癌症、肺癌(Ghé,C.等,Endocrinology,(2002),143(2):484-91)、食道癌(Nwokolo,C.U.等,Gut,(2003),52(5):637-40)、头颈癌(Jozkow,P.等,Head Neck,(2005),27(3):243-7)、造血***癌症、睾丸癌(Gaytan,F.等,J.Clin.Endocri Metab.,(2004),89(1):400-9)、结直肠癌(Dagnaes-Hansen,H.等,Anticancer Res.,(2004),24(6):3735)、***癌(Jeffery,P.L.等,Endocrinology,(2002),172:R7-11)和胰腺癌(Volante,M.等,J.Clin.Endocri.Metab.,(2002),87(3):1300-8);以及国际专利申请号PCT/US2005/016565[WO2005/110463])。
最后,生长素释放肽显示可以治疗炎性疾病(国际专利申请号PCT/US2005/016565[WO 2005/110463]),例如哮喘、反应性关节炎、肝炎(Wallace,J.D.等,J.Clin.Endocri.Metab.,(2002),87(6):2751-9)、椎关节炎、舍格伦综合征、阿尔茨海默氏病(美国专利号6,686,359和6,566,337;以及Obermayr,R.P.等,Gerontology,(2003),49(3):191-5)和特应性皮炎或者与自身免疫病有关的炎性疾病,所述的自身免疫病例如***性红斑狼疮、类风湿性关节炎(Otero,M.等,Rheumatology(Oxford),(2004),43(3):306-10)、***性血管炎、胰岛素依赖型糖尿病(Nieves-Riviera,F.等,Growth Regul.,(1993),3:235-44,)、多发性硬化和肌营养不良症(美国专利 公布号2003/0139348)、实验性过敏脑脊髓炎(Ikushima,H.等,j.Immunol.,(2003),171:2769-72)、银屑病(Edmondson,S.R.等,Endocri.Rev.,(2003),24(6):737-64)、克隆病(Slonim,A.E..等,N.Engl.J.Med.,(2000),342(22):1633-7)、炎性肠病(Chen,K.等,Surgery,(1997),121(2):212-8)、溃疡性结肠炎、艾迪生病(Arvat,E.等,Neuroendocrinology,(1999),70(3):200-6)、斑秃、乳糜泻(Peracchi,M.等,Am.J.Gastroenterol.,(2003),98(11):2474-8);以及Capristo,E.等,Scand.J.Gastroenterol.,(2005),40(4):430-6)、甲状腺病(Riis,A.L.等,J.Clin.Endocrin.Metab.,(2003),88(2):853-7)和硬皮病。源***伤的炎症也可从生长素释放肽治疗中受益,如肺部的炎症(国际专利申请号PCT/US2005/016565[WO2005/110463])。炎症还可以使受试者丧失食欲,特别是当炎症为低度时和/或在老年受试者中时(国际专利申请号PCT/US2005/016565[WO2005/110463])。
生长素释放肽拮抗剂也可以用于在患者中实现有益效果(美国专利公布号2002/187938、2003/0211967和2004/0157227;以及美国专利号6,967,237)。例如,生长素释放肽拮抗剂可以用于促进体重降低或降低食欲、维持理想体重、治疗肥胖、维持糖尿病状态(包括其并发症如视网膜病变)和/或治疗心血管病。过量体重是几种不同疾病或状况的促成因素,所述疾病或状况包括但不限于高血压、糖尿病、血脂异常、心血管病、胆结石形成、骨关节炎和普-威综合征以及某些形式的癌症。体重减轻可以例如用于降低此类疾病的可能性并且成为此类疾病治疗的一部分。
考虑到GHS具有或赋予广泛多样的有益效果,因此本领域需要有效的激动剂或拮抗剂生长素释放肽类似物分子。
发明简述
已经发现,与天然生长素释放肽相比,其中氨基酸残基A15、A16、A17、A18、A19或A20被Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Gly(肉豆蔻基)、Ser(C(O)-R4)、Thr(C(O)-R5)或 HN-CH((CH2)n-N(R12R13))-C(O)、或特别是Lys(生物素基)17或Lys(肉豆蔻基)17取代的生长素释放肽类似物显示具有更高的细胞膜结合亲和力,并且与膜结合受体更有效地相互作用,并且因此具有更高的生物学效力。
根据该发现,本发明的特征在于在GHS受体处具有活性的生长素释放肽类似物,其中氨基酸残基A15、A16、A17、A18、A19或A20被Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Gly(肉豆蔻基)1、Lys(生物素基)17、Lys(肉豆蔻基)17、Ser(C(O)-R4)、Thr(C(O)-R5)或HN-CH((CH2)n-N(R12R13))-C(O)取代。
因此,本发明的第一个方面描述根据式(I)的生长素释放肽类似物或其可药用盐,其中在A1-A28的定义中列出的第一个氨基酸是在天然生长素释放肽序列,即H-Gly-Ser-Ser-Ph e-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg-NH2中该位置中的氨基酸:
(R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A 18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-R1
(I)
其中:
A1是Gly、Acc、Aib、Ala或β-Ala;
A2是Ser、Abu、Acc、Act,Aib、Ala、Ava、Thr或Val;
A3是Ser、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)或HN-CH((CH2)n-N(R12R13))-C(O);
A4是Phe、Acc、Aic、Cha、2-Fua、1-Nal、2-Nal、2-Pal、3-Pal,4-Pal、hPhe、(X1,X2,X3,X4,X5)Phe、Taz、2-Thi、3-Thi、Trp或Tyr;
A5是Leu、Abu、Acc、Aib、Ala、Cha、Ile、hLeu、Nle、Nva、Phe、Tle或Val;
A6是Ser、Abu、Acc、Act、Aib、Ala、Gly、Thr或Val;
A7是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz或Tic;
A8是Glu、Acc、Aib、Arg、Asn、Asp、Dab、Dap、Gln、Lys、Orn或HN-CH((CH2)n-N(R12R13))-C(O);
A9是His、Acc、Apc、Aib、2-Fua、2-Pal、3-Pal、4-Pal、(X1,X2,X3,X4,X5-)Phe、Taz、2-Thi或3-Thi;
A10是Gln、Acc、Aib、Asn、Asp或Glu;
A11是Arg、Apc、hArg、Dab、Dap、Lys、Orn或HN-CH((CH2)n-N(R12R13))-C(O);
A12是Val、Abu、Acc、Aib、Ala、Cha、Gly、Ile、Leu、Nle、Nva或Tle;
A13是Gln、Acc、Aib、Asn、Asp或Glu;
A14是Gln、Acc、Aib、Asn、Asp或Glu;
A15是Arg、Acc、Aib、Apc、hArg、Dab、Dap、Lys、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)或HN-CH((CH2)n-N(R12R13))-C(O);
A16是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A17是Glu、Arg、Asn、Asp、Dab、Dap、Gln、Lys、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Lys(生物素基)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A18是Ser、Abu、Acc、Act、Aib、Ala、Thr、Val、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A19是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A20是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A21是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz、Tic或缺失;
A22是Pro、Dh p、Dmt、3-Hyp、4-Hyp、In c、Ktp、Oic、Pip、Thz、Tic或缺失;
A23是Abu、Acc、Act、Aib、Ala、Apc、Gly、Nva、Val或缺失;
A24是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A25是Leu、Abu、Acc、Aib、Ala、Cha、Ile、hLeu、Nle、Nva、Phe、Tle、Val或缺失;
A26是Gln、Aib、Asn、Asp、Glu或缺失;
A27是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz、Tic或缺失;
A28是Acc、Aib、Apc、Arg、hArg、Dab、Dap、Lys、Orn、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
R1是-OH、-NH2、-(C1-C30)烷氧基或NH-X6-CH2-Z0,其中X6是(C1-C12)烷基或(C2-C12)烯基并且Z0是-H、-OH、-CO2H或-C(O)-NH2;
R2和R3相互独立地选自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(C2-C30)酰基、取代的(C2-C30)烯基、取代的芳基(C1-C30)烷基、取代的(C2-C30)炔基和取代的芳基(C1-C30)酰基;
R4、R5、R6、R7、R8、R9、R10、R11、R14、R15、R16和R17相互独立地选自(C1-C40)烷基、(C2-C40)烯基、取代的(C1-C40)烷基、取代的(C2-C40)烯基、烷基芳基、取代的烷基芳基、芳基和取代的芳基;
R12和R13相互独立地选自H、(C1-C40)烷基、(C1-C40)杂烷基、(C1-C40)酰基、(C2-C40)烯基、(C2-C40)炔基、芳基(C1-C40)烷基、芳基(C1-C40)酰基、取代的(C1-C40)烷基、取代的(C1-C40)杂烷基、取代的(C1-C40)酰基、取代的(C2-C40)烯基、取代的(C2-C40)炔基、取代的芳基(C1-C40)烷基、取代的芳基(C1-C40)酰基、(C1-C40)烷基磺酰基、-C(NH)-NH2和生物素基;
n独立地是1、2、3、4或5;
X1、X2、X3、X4和X5相互独立地选自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和CN;
前提条件是:
(I)当R2是(C1-C30)酰基、芳基(C1-C30)酰基、取代的(C2-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)烯基、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;
(II)当R12是(C1-C40)酰基、芳基(C1-C40)酰基、取代的(C1-C40)酰基、取代的芳基(C1-C40)酰基、(C1-C40)烷基磺酰基或-C(NH)-NH2时,R13是H或(C1-C40)烷基、(C1-C40)杂烷基、(C2-C40)烯基、(C2-C40)炔基、芳基(C1-C40)烷基、取代的(C1-C40)烷基、取代的(C1-C40)杂烷基、取代的(C2-C40)烯基、取代的(C2-C40)炔基或取代的芳基(C1-C40)烷基;
(III)所述生长素释放肽类似物的A15、A16、A17、A18、A19或A20的至少一个选自Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、 hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)和HN-CH((CH2)n-N(R12R13))-C(O);和
(IV)当A15、A16、A17、A19和A20任一个是HN-CH((CH2)n-N(R12R13))-C(O)时,R12必须是生物素基;
一组优选的式(I)化合物(称作组1化合物)是其中:
A1是Gly或Aib;
A2是Ser、Act、Aib、Ava或A5c;
A3是Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)或Ser(C(O)-R4);
A4是Phe;
A5是Leu、Acc、Aib、Cha或hLeu;
A6是Ser、Abu、Act、Aib或Thr;
A7是Pro、Dhp、Dmt、4Hyp、Ktp、Pip或Thz;
A8是Glu或Aib;
A9是His、Aib、Apc、2-Fua、2-Pal、3-Pal、4-Pal、Taz或2-Thi;
A10是Gln或Aib;
A11是Arg;
A12是Val或Acc;
A13是Gln;
A14是Gln;
A15是Arg或Orn;
A16是Lys或Apc;
A17是Glu;
A18是Ser;
A19是Lys;
A20是Lys;
A21是Pro;
A22是Pro;
A23是Ala;
A24是Lys;
A25是Leu;
A26是Gln;
A27是Pro;并且
A28是Arg;
或其可药用盐。
另一组优选的式(I)化合物(称作组2化合物)是其中:
R2和R3相互独立地选自H、酰基、正丁酰基、异丁酰基和正辛酰基;
R4是庚基;
R6是己基;
R7是己基;
R10是辛基;
R11是庚基;以及
前提条件是当Acc取代天然存在残基之一时,Acc每种情况下独立地是A3c、A4c、A5c或A6c;
或其可药用盐。
上面刚刚描述的一组化合物的另一组优选化合物(称作组3化合物)是其中:
A3是Asp(NH-己基)、Asp(1-庚醇)、Cys(S-(CH2)9CH3)、Dap(辛烷磺酰基)、Glu(NH-己基)或Glu(1-庚醇);
A5是Leu;
A6是Ser;
A7是Pro、Dhp、4-Hyp、Pip、Thz或Tic;
A9是His、3-Pal、4-Pal、Taz或2-Thi;
A12是Val;
A15是Arg、Glu(NH-己基)或Ser(正辛酰基);
A16是Lys、Glu(NH-己基)或Ser(正辛酰基);
A17是Glu、Lys(生物素基)、Asp(NH-己基)、Asp(1-庚醇)、Cys(S-(CH2)9CH3)、Dap(辛烷磺酰基)、Glu-(NH-己基)、Glu(1-庚醇)或Ser(正辛酰基);
A18是Ser、Glu(NH-己基)或Ser(正辛酰基);
A19是Lys、Glu(NH-己基)或Ser(正辛酰基);
A20是Lys、Glu(NH-己基)或Ser(正辛酰基);
或其可药用盐。
根据式(I)的更优选的一组化合物(称作组4化合物)包括根据下式的化合物:
(Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:1)
(Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:2)
(Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:3)
(Glu(NH-己基)3,Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:4)
(Aib2,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:5)
(Aib2,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:6)
(Aib2,8,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:7)
(Aib2,8,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:8)
(Aib2,10,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:9)
(Aib2,10,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:10)
(Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:11)
(Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:12)
(Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:13)
(Glu(NH-己基)3,Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:14)
(Aib2,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:15)
(Aib2,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:16)
(Aib2,8,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:17)
(Aib2,8,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:18)
(Aib2,10,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:19)
(Aib2,10,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:20)
(Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:21)
(Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:22)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:23)
(Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:24)
(Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:25)
(Dap(辛烷磺酰基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:26)
(Dap(辛烷磺酰基)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:27)
(Dap(辛烷磺酰基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:28)
(Glu(NH-己基)3,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:29)
(Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:30)
(Cys(S-(CH2)9CH3)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:31)
(Glu(NH-己基)3,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:32)
(Cys(S-(CH2)9CH3)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:33)
(Cys(S-(CH2)9CH3)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:34)
(Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:35)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:36)
(Aib2,Thz7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:37)
(Aib2,4-Hyp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Dhp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Pip7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Tic7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Glu(NH-己基)3,17Thz7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,4-Hyp7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,Dhp7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,Pip7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,Tic7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:39)
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Aib2,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:41)
(Aib2,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:43)
(Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:44)
(Aib8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:45)
(Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(Glu(NH-己基)3,17,Aib8)h生长素释放肽(1-28)-NH2;(SEQ ID NO:47)
(Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Aib1,2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:49)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:51)
(A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:52)
(Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:53)
(Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:54)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:55)
(Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:56)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:57)
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)
(Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:59)
(Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:60)
(Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:61)
(Glu(NH-己基)3,Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:62)
(Aib2,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:63)
(Aib2,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:64)
(Aib2,8,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:65)
(Aib2,8,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:66)
(Aib2,10,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:67)
(Aib2,10,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:68)
(Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:69)
(Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:70)
(Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:71)
(Glu(NH-己基)3,Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:72)
(Aib2,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:73)
(Aib2,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:74)
(Aib2,8,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:75)
(Aib2,8,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:76)
(Aib2,10,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:77)
(Aib2,10,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:78)
(Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:79)
(Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:80)
(Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:81)
(Glu(NH-己基)3,Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:82)
(Aib2,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:83)
(Aib2,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:84)
(Aib2,8,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:85)
(Aib2,8,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:86)
(Aib2,10,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:87)
(Aib2,10,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:88)
(Ac-Gly1,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:89)
(Ac-Gly1,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:90)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:91)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:92)
(Ac-Gly1,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:93)
(Ac-Gly1,Dap(辛烷磺酰基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:94)
(Ac-Gly1,Dap(辛烷磺酰基)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:95)
(Ac-Gly1,Dap(辛烷磺酰基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:96)
(Ac-Gly1,Glu(NH-己基)3,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:97)
(Ac-Gly1,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:98)
(Ac-Gly1,Cys(S-(CH2)9CH3)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:99)
(Ac-Gly1,Glu(NH-己基)3,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:100)
(Ac-Gly1,Cys(S-(CH2)9CH3)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:101)
(Ac-Gly1,Cys(S-(CH2)9CH3)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH(SEQ ID NO:102)
(Ac-Gly1,Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:103)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:104)
(Ac-Gly1,Aib2,Thz7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
(Ac-Gly1,Aib2,4-Hyp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
(Ac-Gly1,Aib2,Dhp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
(Ac-Gly1,Aib2,Pip7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:105)
(Ac-Gly1,Aib2,Tic7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:105)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Thz7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,4-Hyp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Dhp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Pip7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Tic7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:107)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:108)
(Ac-Gly1,Aib2,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:111)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:112)
(Ac-Gly1,Aib8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:113)
(Ac-Gly1,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,Glu(NH-己基)3,17,Aib8)h生长素释放肽(1-28)-NH2;(SEQ IDNO:115)
(Ac-Gly1,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:116)
(Ac-Gly1,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQID NO:116)
(Ac-Gly1,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQID NO:116)
(Ac-Gly1,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQID NO:116)
(Ac-Aib1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:117)
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)
(Ac-Gly1,A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:119)
(Ac-Gly1,A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:120)
(Ac-Gly1,Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:121)
(Ac-Gly1,Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:122)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:123)
(Ac-Gly1,Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:124)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:125)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH(SEQ ID NO:126)
(Ac-Gly1,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:127)
(Ac-Gly1,Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:128)
(Ac-Gly1,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:129)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQNO:130)
(Ac-Gly1,Aib2,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:131)
(Ac-Gly1,Aib2,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:132)
(Ac-Gly1,Aib2,8,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:133)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQID NO:134)
(Ac-Gly1,Aib2,10,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:135)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQID NO:136)
(Ac-Gly1,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:137)
(Ac-Gly1,Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:138)
(Ac-Gly1,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:139)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:140)
(Ac-Gly1,Aib2,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:141)
(Ac-Gly1,Aib2,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:142)
(Ac-Gly1,Aib2,8,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:143)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQID NO:144)
(Ac-Gly1,Aib2,10,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:145)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQID NO:146)
(Ac-Gly1,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:147)
(Ac-Gly1,Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:148)
(Ac-Gly1,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:149)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SID NO:150)
(Ac-Gly1,Aib2,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:151)
(Ac-Gly1,Aib2,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:152)
(Ac-Gly1,Aib2,8,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:153)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQID NO:154)
(Ac-Gly1,Aib2,10,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:155)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQID NO:156)
(Ac-Gly1,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:157)
(Ac-Gly1,Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:158)
(Ac-Gly1,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:159)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEID NO:160)
(Ac-Gly1,Aib2,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:161)
(Ac-Gly1,Aib2,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:162)
(Ac-Gly1,Aib2,8,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:163)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQID NO:164)
(Ac-Gly1,Aib2,10,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:165)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQID NO:166)
(Ac-Gly1,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:167)
(Ac-Gly1,Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:168)
(Ac-Gly1,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:169)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEID NO:170)
(Ac-Gly1,Aib2,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:171)
(Ac-Gly1,Aib2,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:172)
(Ac-Gly1,Aib2,8,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:173)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQID NO:174)
(Ac-Gly1,Aib2,10,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:175)和
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQID NO:176)
或其可药用盐。
根据式(I)的仍然更优选的一组化合物(称作组5)包括根据下式的化合物:
(Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:21)
(Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:22)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:23)
(Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:24)
(Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:25)
(Dap(辛烷磺酰基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:26)
(Dap(辛烷磺酰基)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:27)
(Dap(辛烷磺酰基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:28)
(Glu(NH-己基)3,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:29)
(Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:30)
(Cys(S-(CH2)9CH3)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:31)
(Glu(NH-己基)3,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:32)
(Cys(S-(CH2)9CH3)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:33)
(Cys(S-(CH2)9CH3)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:34)
(Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:35)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:36)
(Aib2,Thz7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,4-Hyp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Dhp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Pip7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Tic7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:37)
(Aib2,Glu(NH-己基)3,17,Thz7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,4-Hyp7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,Dhp7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,Pip7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,Glu(NH-己基)3,17,Tic7)h生长素释放肽(1-28)-NH2;(SEQ IDNO:38)
(Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:39)
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Aib2,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:41)
(Aib2,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:42)
(Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:43)
(Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:44)
(Aib8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:45)
(Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
(Glu(NH-己基)3,17,Aib8)h生长素释放肽(1-28)-NH2;(SEQ ID NO:47)
(Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:48)
(Aib1,2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:49)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:51)
(A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:52)
(Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:53)
(Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:54)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:55)
(Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:56)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:57)
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)
(Ac-Gly1,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:89)
(Ac-Gly1,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:90)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:91)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:92)
(Ac-Gly1,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:93)
(Ac-Gly1,Dap(辛烷磺酰基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:94)
(Ac-Gly1,Dap(辛烷磺酰基)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:95)
(Ac-Gly1,Dap(辛烷磺酰基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:96)
(Ac-Gly1,Glu(NH-己基)3,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:97)
(Ac-Gly1,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:98)
(Ac-Gly1,Cys(S-(CH2)9CH3)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:99)
(Ac-Gly1,Glu(NH-己基)3,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2 (SEQ ID NO:100)
(Ac-Gly1,Cys(S-(CH2)9CH3)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SID NO:101)
(Ac-Gly1,Cys(S-(CH2)9CH3)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH(SEQ ID NO:102)
(Ac-Gly1,Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:103)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:104)
(Ac-Gly1,Aib2,Thz7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
(Ac-Gly1,Aib2,4-Hyp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
(Ac-Gly1,Aib2,Dhp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
(Ac-Gly1,Aib2,Pip7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:105)
(Ac-Gly1,Aib2,Tic7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:105)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Thz7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,4-Hyp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Dhp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Pip7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Tic7)h生长素释放肽(1-28)-NH2; (SEQ ID NO:106)
(Ac-Gly1,Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:107)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:108)
(Ac-Gly1,Aib2,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
(Ac-Gly1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:111)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:112)
(Ac-Gly1,Aib8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:113)
(Ac-Gly1,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:114)
(Ac-Gly1,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:114)
(Ac-Gly1,Glu(NH-己基)3,17,Aib8)h生长素释放肽(1-28)-NH2;(SEQ IDNO:115)
(Ac-Gly1,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ IDNO:116)
(Ac-Gly1,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQID NO:116)
(Ac-Gly1,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQID NO:116)
(Ac-Gly1,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQID NO:116)
(Ac-Aib1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:117)
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)
(Ac-Gly1,A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:119)
(Ac-Gly1,A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:120)
(Ac-Gly1,Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:121)
(Ac-Gly1,Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:122)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:123)
(Ac-Gly1,Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:124)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:125)和
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:126)
或其可药用盐。
根据式(I)的依然更优选的一组化合物(称作组6化合物)包括根据下式的化合物:
(Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:21)
(Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:22)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:23)
(Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:24)
(Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:35)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:36)
(Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:39)
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:43)
(Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:44)
(Aib1,2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:49)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:51)
(A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:52)
(Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:53)
(Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:54)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:55)
(Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:56)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:57)
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)
(Ac-Gly1,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:89)
(Ac-Gly1,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:90)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:91)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:92)
(Ac-Gly1,Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:103)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:104)
(Ac-Gly1,Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:107)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:108)
(Ac-Gly1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:111)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:112)
(Ac-Aib1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:117)
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)
(Ac-Gly1,A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:119)
(Ac-Gly1,A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:120)
(Ac-Gly1,Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:121)
(Ac-Gly1,Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:122)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:123)
(Ac-Gly1,Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:124)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:125)和
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:126)
或其可药用盐。
根据式(I)的依然更优选的一组化合物(称作组7化合物)括根据下式的化合物:
(Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:21)
(Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:22)
(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:23)
(Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:24)
(Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:35)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:36)
(Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:39)
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:43)
(Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:44)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:51)
(A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:52)
(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:36)
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)
(Ac-Gly1,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:89)
(Ac-Gly1,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:90)
(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:91)
(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:92)
(Ac-Gly1,Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:103)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:104)
(Ac-Gly1,Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:107)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:108)
(Ac-Gly1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:111)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:112)
(Ac-Aib1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:117)
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)
(Ac-Gly1,A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:119)
(Ac-Gly1,A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:120)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:125)或
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:126)
或其可药用盐。
根据式(I)的一组优选的化合物(称作组8化合物)包括根据下式的化合物:
A1是Ac-Gly、Ac-Aib或Aib;
A2是Aib;
A3是Glu(NH-己基);
A8是Aib;
A10是Aib;和
A17是Glu(NH-己基)或Lys(生物素基);
或其可药用盐。
更优选的一组刚刚描述的根据式(I)的化合物(称作组9化合物)包括这样的化合物或其可药用盐,其中R2和R3独立地选自H、酰基、正丁酰基、异丁酰基和正辛酰基并且R1是NH2。
甚至更优选的一组刚刚描述的根据式(I)的化合物(称作组10化合物)包括根据下式的化合物:
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:104)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:108)
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:112)
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)和
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:126)
或其可药用盐。
并且甚至更优选的一组刚刚描述的根据式(I)的化合物(称作组11化合物)包括根据下式的化合物:
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)和
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)
或其可药用盐。
并且甚至更优选的一组刚刚描述的根据式(I)的化合物(称作组12化合物)包括根据下式的化合物:
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)
或其可药用盐。
本发明的第二个方面描述根据式(II)的生长素释放肽类似物:1-(R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A 19-A20-A21-A22-A23-A24-A25-A26-A27-A28-R1
(II)
其中:
A1是Gly、Acc、Aib、Ala、β-Ala或Gly(肉豆蔻基);
A2是Ser、Abu、Acc、Act、Aib、Ala、Ava、Thr或Val;
A3是Ser、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)或HN-CH((CH2)n-N(R12R13))-C(O);
A4是Phe、Acc、Aic、Ch a、2-Fu a、1-Nal、2-Nal、2-Pal、3-Pal、4-Pal、hPhe、(X1、X2、X3、X4、X5)Phe、Taz、2-Thi、3-Thi、Trp或Tyr;
A5是Leu、Abu、Acc、Aib、Ala、Ch a、Ile、hLeu、Nle、Nva、Phe、Tle或Val;
A6是Ser、Abu、Acc、Act、Aib、Ala、Gly、Thr或Val;
A7是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz或Tic;
A8是Glu、Acc、Aib、Arg、Asn、Asp、Dab、Dap、Gln、Lys、Orn或HN-CH((CH2)n-N(R12R13))-C(O);
A9是His、Acc、Aib、Apc、2-Fua、2-Pal、3-Pal、4-Pal、(X1、X2、X3、X4、X5-)Phe、Taz、2-Thi或3-Thi;
A10是Gln、Acc、Aib、Asn、Asp或Glu;
A11是Arg、Apc、hArg、Dab、Dap、Lys、Orn或HN-CH((CH2)n-N(R12R13))-C(O);
A12是Val、Abu、Acc、Aib、Ala、Cha、Nva、Gly、Ile、Leu、Nle或Tle;
A13是Gln、Acc、Aib、Asn、Asp或Glu;
A14是Gln、Acc、Aib、Asn、Asp或Glu;
A15是Arg、Acc、Aib、Apc、hArg、Dab、Dap、Lys、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)或HN-CH((CH2)n-N(R12R13))-C(O);
A16是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、 Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A17是Glu、Arg、Asn、Asp、Dab、Dap、Gln、Lys、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Lys(生物素基)、Lys(肉豆蔻基)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A18是Ser、Abu、Acc、Act、Aib、Ala、Thr、Val、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A19是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A20是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A21是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz、Tic或缺失;
A22是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz、Tic或缺失;
A23是Abu、Acc、Act、Aib、Ala、Apc、Gly、Nva、Val或缺失;
A24是Lys、Acc、Aib、Apc、Arg、hArg、Dab、Dap、Orn、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
A25是Leu、Abu、Acc、Aib、Ala、Cha、Ile、hLeu、Nle、Nva、Phe、Tle、Val或缺失;
A26是Gln、Aib、Asn、Asp、Glu或缺失;
A27是Pro、Dhp、Dmt、3-Hyp、4-Hyp、Inc、Ktp、Oic、Pip、Thz、Tic或缺失;
A28是Acc、Aib、Apc、Arg、hArg、Dab、Dap、Lys、Orn、HN-CH((CH2)n-N(R12R13))-C(O)或缺失;
R1是-OH、-NH2、-(C1-C30)烷氧基或NH-X6-CH2-Z0,其中X6是(C1-C12)烷基或(C2-C12)烯基并且Z0是-H、-OH、-CO2H或-C(O)-NH2;
R2和R3相互独立地选自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(C2-C30)酰基、取代的(C2-C30)烯基、取代的芳基(C1-C30)烷基、取代的(C2-C30)炔基和取代的芳基(C1-C30)酰基或可以缺失;
R4、R5、R6、R7、R8、R9、R10、R11、R14、R15、R16和R17相互独立地选自(C1-C40)烷基、(C2-C40)烯基、取代的(C1-C40)烷基、取代的(C2-C40)烯基、烷基芳基、取代的烷基芳基、芳基和取代的芳基;
R12和R13相互独立地选自H、(C1-C40)烷基、(C1-C40)杂烷基、(C1-C40)酰基、(C2-C40)烯基、(C2-C40)炔基、芳基(C1-C40)烷基、芳基(C1-C40)酰基、取代的(C1-C40)烷基、取代的(C1-C40)杂烷基、取代的(C1-C40)酰基、取代的(C2-C40)烯基、取代的(C2-C40)炔基、取代的芳基(C1-C40)烷基、取代的芳基(C1-C40)酰基、(C1-C40)烷基磺酰基、-C(NH)-NH2和生物素基;
n独立地是1、2、3、4或5;
X1、X2、X3、X4和X5相互独立地选自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和CN;
前提条件是:
(I)当R2是(C1-C30)酰基、芳基(C1-C30)酰基、取代的(C2-C30)酰基或取代的芳基(C1-C30)酰基时,则R3是H、(C1-C30)烷基、(C1-C30)杂烷基、(C2-C30)烯基、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;
(II)当R12是(C1-C40)酰基、芳基(C1-C40)酰基、取代的(C1-C40)酰基、取 代的芳基(C1-C40)酰基、(C1-C40)烷基磺酰基或-C(NH)-NH2时,则R13是H或(C1-C40)烷基、(C1-C40)杂烷基、(C2-C40)烯基、(C2-C40)炔基、芳基(C1-C40)烷基、取代的(C1-C40)烷基、取代的(C1-C40)杂烷基、取代的(C2-C40)烯基、取代的(C2-C40)炔基或取代的芳基(C1-C40)烷基;
(III)所述生长素释放肽类似物的A15、A16、A17、A18、A19或A20中至少一个选自Asp(NH-R9)、Asp(O-R8)、Cys(S-R14)、Cys(R15)、hCys(S-R16)、hCys(R17)、Dab(S(O)2-R11)、Dap(S(O)2-R10)、Glu(NH-R7)、Glu(O-R6)、Ser(C(O)-R4)、Thr(C(O)-R5)或HN-CH((CH2)n-N(R12R13))-C(O);和
(IV)当A15、A16、A17、A19和A20的任一个是HN-CH((CH2)n-N(R12R13))-C(O)时,则R12必须是生物素基;
或其可药用盐。
一组优选的式(II)化合物(称作组13化合物)是其中:
A1是Gly或Gly(肉豆蔻基);
A2是Ser或Aib;和
A17是Ser(正辛酰基)或Lys(肉豆蔻基);
或其可药用盐。
另一组仍然优选的式(II)化合物(称作组14化合物)是其中:
A17是Lys(肉豆蔻基)。
刚刚描述化合物的一组更优选的化合物(称作组15化合物)是其中:
R2选自H、酰基、正丁酰基、异丁酰基、正辛酰基和肉豆蔻基;
R3缺失;
R4是庚基;
R6是己基;
R7是己基;
R10是辛基;和
R11是庚基;
前提条件是当Acc取代序列的天然存在残基的任意一个时,Acc在每种情况下独立地选自A3c、A4c、A5c和A6c;
或其可药用盐。
甚至更优选的根据式(II)的化合物(称作组16化合物)包括根据下式的化合物:
(Aib2,Lys(肉豆蔻基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:177)和
(Gly(肉豆蔻基)1,Aib2,Lys(肉豆蔻基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:178)
或其可药用盐。
在另一方面,本发明提供药物组合物,包含有效量的式(I)或(II)的化合物、更优选根据如上所定义的组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16的一组或一组以上的化合物或其可药用盐和可药用载体或稀释剂。
本文描述的生长素释放肽类似物在GHS受体处是有活性的。类似物可以结合至受体并且刺激或抑制受体活性。生长素释放肽类似物具有多种不同的用途,包括但不限于用作研究工具或者用作治疗剂。
研究工具应用一般涉及生长素释放肽类似物的用途和GHS受体或其片段的存在。GHS受体可以存在于不同的环境中,例如哺乳动物受试者、完整细胞或膜碎片中。研究工具应用的实例包括但不限于筛选在GHS受体处具有活性的化合物、确定样品或制备物中GHS受体的存在和检查生长素释放肽的作用或效果。
生长素释放肽类似物可用于筛选生长素释放肽激动剂和生长素释放肽拮抗剂。对生长素释放肽激动剂的筛选可以例如通过在具有测试化合物的竞争实验中使用生长素释放肽类似物来开展。对生长素释放肽拮抗剂的筛选可以例如通过使用生长素释放肽类似物以产生GHS受体活性然后测定化合物改变GHS受体活性的能力来开展。
本发明另一方面的特征在于用于筛选能够结合至GHS受体的化合物的方法。方法包括步骤:测定化合物影响生长素释放肽类似物与受体、包含生长素释放肽结合位点的受体片段、包含所述片段的多肽或所述多肽的 衍生物的结合的能力。对于筛选有用的化合物包括式(I)或(II)所包括的化合物、更优选根据上面所定义组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐和可药用载体或稀释剂。
本发明另一方面的特征在于用于在受试者中实现有益效果的方法,包括向所述受试者施用有效量的一种或一种以上根据式(I)或(II)的化合物、优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中一组或一组以上的化合物或其可药用盐,其中所述有效量对于在帮助治疗(例如治愈或降低严重性)或预防(例如降低发作的可能性或严重性)疾病或者病症中产生有益效果而言是有效的。
生长素释放肽以剂量依赖性方式诱导GH从原代培养垂体细胞中释放,而不刺激释放其它垂体激素。当将生长素释放肽静脉注射进入麻醉的大鼠中后,生长素释放肽刺激脉冲式释放GH(Kojima,M.等,Nature,(1999),402(6762):656-60),因此本发明另一方面的特征在于用于在需要其的受试者中刺激GH分泌的方法,包括施用有效量的一种或一种以上根据式(I)或(II)的化合物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐,其中有效量是至少足以产生可检测的GH分泌增加的量,并且优选地是足以在患者中实现有益效果的量。
刚刚描述方法的一个优选方法是,其中所述的对GH分泌的刺激适应于治疗GH不足状态、增加肌肉质量和/或骨密度、克服性功能障碍、增加体重和/或维持理想体重、维持和/或恢复身体机能和/或增加食欲。
刚刚描述方法的一个优选方法是,其中所述体重的增加或其维持或食欲增加表明患者具有疾病或病症或者经历伴有体重减轻的治疗。
刚刚描述方法的一个优选方法是,其中伴有体重减轻的所述疾病与恶病质的发作有关,所述恶病质包括但不限于厌食症、贪食症、癌症、艾滋病和慢性阻塞性肺疾病(COPD)。刚刚描述方法的另一方面是其中所述体 重降低是因为消瘦综合征的发作,特别是在虚弱或老人中。刚刚描述方法的另一个优选方法是在健康老年患者的未明体重降低之后促进体重增加,或者预防、治疗或者减轻阿尔茨海默氏病发作。刚刚描述方法的另一个仍优选的方法是其中伴有体重降低的治疗包括化学疗法、放射疗法、暂时固定、永久固定和透析。
刚刚描述方法的另一个优选方法是,其中所述体重增加或其维持和/或食欲增加表明健康患者未患有特定疾病或病症或者经历上述治疗。
本文描述的生长素释放肽类似物还可以体外和体内拮抗生长素释放肽的作用,因此本发明另一方面的特征在于用于通过施用有效量的根据式(I)或(II)的一种或一种以上化合物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐在需要其的受试者中抑制GH分泌的方法,其中所述有效量是至少足以产生GH分泌可检测的降低的量,并且优选是在患者中实现有益效果的量。
刚刚描述方法的一个优选方法是,其中所述的对GH分泌的抑制适应于治疗过量GH分泌、降低体重、降低食欲、维持理想体重、克服肥胖、控制糖尿病及其并发症如视网膜病变和/或治疗心血管病。
当体重过量增加是包括但不限于高血压、糖尿病、血脂异常、心血管病、胆结石、骨关节炎和某些癌症的疾病或病症的促成因素时,特别是其中所述体重降低降低了此类疾病的可能性或者包含对于此类疾病或状况的至少部分治疗时,刚刚描述方法是优选的。
根据式(I)或(II)的生长素释放肽激动剂或类似物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物可用于在受试者中实现有益效果,例如下列的一种或一种以上:治疗GH不足状态、增加肌肉质量和/或骨密度、克服性功能障碍、促进体重增加、维持理想体重、恢复和/或复原正常身体机能和/或增加食欲。促进体重增加、维持体重和/或增加食欲特别用于治疗患有恶病质或与疾病或病症有关的消瘦综合征或 经历通常伴有体重降低的医学或治疗方案的患者。源于恶病质的伴有体重降低的疾病或病症的实例包括厌食症、贪食症、癌症和艾滋病。增加体重、维持理想体重或增加食欲特别有益于患有消瘦综合征的患者,特别是虚弱和老年的患者。伴有体重降低的治疗的实例包括化学疗法、放射疗法、暂时或永久固定和/或透析。
根据式(I)或(II)的生长素释放肽激动剂或类似物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物已经成功用于治疗患有术后肠梗阻或慢性阻塞性肺疾病的受试者。
此外,生长素释放肽在治疗哺乳动物受试者炎症中是有效的。因此,在本发明的一个方面中,本发明提供了用于通过施用有效量的根据式(I)或(II)的一种或一种以上化合物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐治疗需要其的受试者中炎症的方法,其中所述有效量是至少足以产生可检测的炎症减轻的量并且优选是在患者中实现有益效果的量。
在刚刚描述方法的一个方面中,炎症与病毒、细菌、寄生虫或真菌感染有关。在上述方法的一个方面中,炎症与病毒感染有关。可用生长素释放肽、生长素释放肽类似物和/或生长素释放肽激动剂治疗的病毒感染包括但不限于单纯疱疹病毒1型、单纯疱疹病毒2型、巨细胞病毒、EB病毒、水痘-带状疱疹病毒、人疱疹病毒6、人疱疹病毒7、人疱疹病毒8、天花病毒、水疱性口炎病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒、鼻病毒、冠状病毒、甲型流感病毒、乙型流感病毒、麻疹病毒、多瘤病毒、人***瘤病毒、呼吸道合胞病毒、腺病毒、柯萨奇病毒、登革热病毒、腮腺炎病毒、脊髓灰质炎病毒、狂犬病病毒、劳斯肉瘤病毒、黄热病毒、埃波拉病毒、马尔堡病毒、拉沙热病毒、东方马脑炎病毒、日本脑炎病毒、圣路易斯脑炎病毒、墨累山谷热病毒、西尼罗病毒、立夫特山谷热病毒、轮状病毒A、轮状病毒B、轮状病毒C、Sindbis 病毒、猿猴免疫缺陷病毒、人T细胞白血病病毒1型、汉坦病毒、风疹病毒、猿猴免疫缺陷病毒、人免疫缺陷病毒1型和/或人免疫缺陷病毒2型。
在上述方法的另一个方面中,炎症与细菌感染有关。导致可以用生长素释放肽、一种或一种以上生长素释放肽类似物或生长素释放肽激动剂治疗的炎症的细菌感染包括但不限于结核分枝杆菌、牛分枝杆菌、牛分枝杆菌BCG株、BCG亚株、鸟分枝杆菌、胞内分枝杆菌、非洲分枝杆菌、堪萨斯分枝杆菌、海分枝杆菌、溃疡分枝杆菌、鸟分枝杆菌副结核亚型、星型诺卡氏菌、其它诺卡尔菌物种、嗜肺军团菌、其它军团菌物种、伤寒沙门氏菌、其它沙门氏菌物种、志贺氏菌、鼠疫耶尔森氏菌、溶血巴斯德菌、多杀巴斯德菌、其它巴斯德菌物种、胸膜炎肺炎放线杆菌、单核细胞增生利斯特氏菌、绵羊利斯特氏菌、流产布鲁氏菌、其它布鲁氏菌物种、反刍类考德里氏体、肺炎衣原体、沙眼衣原体、鹦鹉衣原体、贝纳柯克斯体、其它立克次体物种、埃里希氏体物种、金黄色葡萄球菌、表皮葡萄球菌、酿脓链球菌、无乳链球菌、炭疽芽孢杆菌、大肠杆菌、霍乱弧菌、弯曲杆菌物种、脑膜炎奈瑟氏菌、淋病奈瑟氏菌、铜绿假单胞菌、其它假单胞菌物种、流感嗜血菌、杜克雷嗜血杆菌、其它假单胞菌物种、破伤风梭菌、其它梭菌物种、小肠结肠炎耶尔森氏菌和/或其它耶尔森氏菌物种。
在上述方法的另一方面中,炎症与寄生虫或真菌感染有关。可以用生长素释放肽、一种或一种以上生长素释放肽类似物或生长素释放肽激动剂治疗的寄生虫感染包括但不限于鼠弓形虫、疟原虫属、布鲁斯锥虫、克鲁斯锥虫、利什曼原虫属、血吸虫属和/或溶组织内阿米巴。可以用生长素释放肽、生长素释放肽类似物或生长素释放肽激动剂治疗的真菌感染包括但不限于白色念珠菌、新型隐球菌、荚膜组织胞浆菌、烟曲霉、粗球类芽生菌、巴西副球孢子菌、皮炎芽生菌、卡氏肺孢菌、马尔尼菲青霉和/或细链格孢菌。
在本发明的另一方面中,由肝脏毒性或移植排斥导致的炎症也可以通过施用有效量的根据式(I)或(II)的一种或一种以上化合物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、 组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐治疗,其中所述有效量是至少足以产生可检测的炎症减轻的量并且优选是在患者中实现有益效果的量。肝脏毒性可以与癌症治疗有关。在一些情况下,癌症治疗如化学疗法可以产生肝脏毒性。通过化学疗法和细胞凋亡产生的肝脏毒性可以通过施用生长素释放肽、生长素释放肽激动剂和/或生长素释放肽拮抗剂治疗。
在本发明的另一方面,与癌症有关的炎症也可以通过施用有效量的根据式(I)或(II)的一种或一种以上化合物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐治疗,其中所述有效量是至少足以产生可检测的炎症减轻的量并且优选是在患者中实现有益效果的量。此类癌症包括但不限于淋巴瘤、白血病、蕈样肉芽肿、癌、腺癌、肉瘤、神经胶质瘤、胚细胞瘤、成神经细胞瘤、浆细胞瘤、组织细胞瘤、黑素瘤、腺瘤、乏氧肿瘤、骨髓瘤、艾滋病相关淋巴瘤或艾滋病相关肉瘤、转移癌、膀胱癌、脑癌、神经***癌症、成胶质细胞瘤、卵巢癌、皮肤癌、肝癌、口腔、咽、喉、和肺的鳞状上皮细胞癌、结肠癌、***、乳腺癌、上皮癌、肾癌、泌尿生殖器癌症、肺癌、食道癌、头颈癌、造血***癌症、睾丸癌、结直肠癌、***癌和/或胰腺癌。
在本发明的另一个方面中,炎性疾病还可以通过施用有效量的根据式(I)或(II)的一种或一种以上化合物、更优选根据组1、组2、组3、组4、组5、组6、组7、组8、组9、组10、组11、组12、组13、组14、组15和/或组16中的一组或一组以上的化合物或其可药用盐治疗,其中所述有效量是至少足以产生可检测的炎症减轻的量并且优选是在患者中实现有益效果的量。可通过本发明的生长素释放肽、一种或一种以上生长素释放肽激动剂和/或生长素释放肽拮抗剂治疗的炎性疾病包括但不限于哮喘、反应性关节炎、肝炎、椎关节炎、舍格伦综合征、阿尔茨海默氏病、和特应性皮炎或与自身免疫病有关的炎性疾病,所述自身免疫病例如***性红斑狼疮、类风湿性关节炎、***性血管炎、胰岛素依赖型糖尿病、多发性硬化、肌 营养不良症、实验性过敏脑脊髓炎、银屑病、克隆病、炎性肠病、溃疡性结肠炎、艾迪生病、斑秃、乳糜泻、甲状腺病和/或硬皮病。源于烧伤的炎症也可以从用生长素释放肽、一种或一种以上生长素释放肽激动剂和/或一种或一种以上生长素释放肽拮抗剂的治疗中受益。肺的炎症也可以用生长素释放肽、一种或一种以上生长素释放肽激动剂和/或一种或一种以上生长素释放肽拮抗剂治疗。炎症还可以导致受试者降低食欲,特别是当炎症为低度时和/或在老年受试者中时。
生长素释放肽拮抗剂可用于在患者中实现有益效果。例如,生长素释放肽拮抗剂可用于促进体重降低和/或降低食欲、维持理想体重、逆转肥胖、治疗糖尿病和其并发症如视网膜病变和/或改善心血管疾病。过量体重是包括但不限于高血压、糖尿病、血脂异常、心血管病、胆结石形成、骨关节炎、普-威综合征和/或某些形式的癌症的不同疾病的促成因素。当用作此类疾病的部分处方疗法时,体重降低证明减小了此类疾病的可能性。
本发明的其它特征和优点根据本文提供的包括不同的实施例的另外的描述是显而易见的。所提供的实施例说明了在实践本发明中有用的不同的成分和方法学。实施例不限制所要求保护的发明。基于本公开,技术人员可以鉴定和采用对于实践本发明有用的其它成分和方法学。
发明详述
本发明特征在于在GHS受体处具有活性的生长素释放肽类似物。人生长素释放肽是28个氨基酸的修饰肽,其中丝氨酸羟基被正辛酸酯化。(Kojima,M.等,Nature,(1999),402(6762):656-60以及Kojima,M.(摘要),第三届生长激素促分泌剂国际会议,美国科罗拉多Keystone,2000年2月17-19日)。
如上面所详述,本发明的类似物可用于治疗受试者中的广泛多种的疾病。“受试者”如本文和该申请通篇所使用,指哺乳动物或非哺乳动物,包括例如但不限于人、大鼠、小鼠或农场动物。提及受试者无需指出存在疾病或病症。术语“受试者”包括例如作为实验一部分给予生长素释放肽类似 物的哺乳动物或非哺乳动物、被治疗以帮助缓解疾病或病症的哺乳动物或非哺乳动物和被预防性治疗以延缓或预防疾病或病症发作的哺乳动物或非哺乳动物。
本发明化合物或组合物的“治疗接受量”,不管制剂或施用途径如何,是在受试者中引起目的生物学反应的量。治疗量的生物学效应可在生物的多种水平上出现和测量。例如,治疗量的生物学效应可以在细胞水平出现并且可以通过测量结合生长素释放肽和/或生长素释放肽类似物的受体处反应在细胞水平上测定,或者治疗量的生物学效应可以在***水平上出现和测量,例如影响循环生长激素水平的增加/降低。治疗量的生物学效应可以在器官水平出现和测量,例如缓解受试者中疾病或病症的症状或进展。本发明化合物或组合物的治疗接受量,不管制剂或施用途径如何,可导致在受试者中产生一种或一种以上生物学反应。在本发明的化合物或组合物在体外***中接受测试的情况下,化合物或组合物的治疗接受量可以看作是在所选择体外***中产生可测量反应的量。
除非另外定义,本文所用的所有技术和科学术语具有与本发明所属领域中普通技术人员通常理解的含义相同的含义。同样,将本文提到的所有出版物、专利申请、专利和其它参考文献引入作为参考。
本发明化合物中存在的某些氨基酸表示于下文:
名词和缩写
符号 含义
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 表示结构
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
Apc 表示结构:
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
Ava 5-氨基-n-戊酸
Cha β-环己基丙氨酸
Cys或C 半胱氨酸
hCys L-高半胱氨酸
Dab 2,4-二氨基丁酸
Dap 2,3-二氨基丙酸
Dhp 3,4-脱氢脯氨酸
Dmt 5,5-二甲基噻唑烷-4-羧酸
2-Fua β-(2-呋喃基)-丙氨酸
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
3-Hyp 反式-3-羟基-L-脯氨酸,即(2S,3S)-3-羟基吡咯烷-2-羧酸
4-Hyp 4-羟基脯氨酸,即(2S,4R)-4-羟基吡咯烷-2-羧酸
Ile或I 异亮氨酸
Inc 二氢吲哚-2-羧酸
Inp 4-哌啶甲酸
Ktp 4-酮脯氨酸
Leu或L 亮氨酸
hLeu 高亮氨酸
Lys或K 赖氨酸
Met或M 甲硫氨酸
1-Nal β-(1-萘基)-L-丙氨酸
2-Nal β-(2-萘基)-L-丙氨酸
Nle 正亮氨酸
Nva 正缬氨酸
Oic 八氢吲哚-2-羧酸
Orn 鸟氨酸
2-Pal β-(2-吡啶基)丙氨酸
3-Pal β-(3-吡啶基)丙氨酸
4-Pal β-(4-吡啶基)丙氨酸
Phe或F 苯丙氨酸
hPhe 高苯丙氨酸
Pip 2-哌啶酸
Pro或P 脯氨酸
Ser或S 丝氨酸
Taz β-(4-噻唑基)丙氨酸,即
2-Thi β-(2-噻吩基)丙氨酸
3-Thi β-(3-噻吩基)丙氨酸
Thp 4-氨基-4-羧基四氢吡喃
Thr或T 苏氨酸
Thz 噻唑烷-4-羧酸
Tic 1,2,3,4-四氢异喹啉-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
当氨基酸具有异构形式时,除非另外明确指出,否则其为L型氨基酸。用于定义肽的术语是在本领域中通常所用的那些,其中N-末端的氨基出现在左边并且C-末端的羧基出现在右边,即代表结构-NH-CI(R’)-CO-,其中R和R’每一个独立地是氢或氨基酸侧链(例如对于Ala,R=CH3和R’=H)或R和R’可以连接形成环***。对于N-末端氨基酸,缩写代表结构:
本发明的肽在本文中还可以通过另一种形式表示,例如(Aib2)h生长素释放肽(1-28)-NH2,其中取代天然序列的氨基酸置于第一组括号内(例如在h生长素释放肽中Aib2替代Ser2)。第二组括号内的数字指肽中所存在的氨基酸的数目(例如,h生长素释放肽(1-18)指人生长素释放肽的肽序列氨基酸1-18)。名称“NH2”,例如在(Aib2)h生长素释放肽(1-28)-NH2中,标 明肽的C-末端被酰胺化。(Aib2)h生长素释放肽(1-28)或者备选地(Aib2)h生长素释放肽(1-28)-OH标明C-末端是游离酸。插在“生长素释放肽”之前的小写字母表示其来源或起源,即“h ”表示生长素释放肽是在人物种中发现的生长素释放肽的同源物。
除非另外说明,这些具有手性中心的氨基酸以L-对映异构体提供。提及“其衍生物”时指修饰的氨基酸,例如相应的D-氨基酸、N-烷基-氨基酸、β-氨基酸或标记的氨基酸。
如本文中所使用,Acc包括选自1-氨基-1-环丙烷羧酸(A3c);1-氨基-1-环丁烷羧酸(A4c);1-氨基-1-环戊烷羧酸(A5c);1-氨基-1-环己烷羧酸(A6c);1-氨基-1-环庚烷羧酸(A7c);1-氨基-1-环辛烷羧酸(A8c);以及1-氨基-1-环壬烷羧酸(A9c)的氨基酸。
“酰基”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、烯基、取代的烯基、芳基、烷基芳基或取代的烷基芳基。
“烷基”指包含一个或一个以上碳原子的烃基团,其中如果存在多个碳原子的话,则多个碳原子通过单键连接。烷基烃基团可以是直链的或者包含一个或一个以上分支或环状基团。
“取代的烷基”指其中烃基团的一个或一个以上氢原子被一个或一个以上取代基取代的烷基,所述取代基选自卤素(即氟、氯、溴和碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、用1-6个卤素取代的-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的存在导致产生烷基酸。包含-(CH2)0-20-COOH或由其组成的烷基酸实例包括但不限于2-降冰片烷乙酸、叔丁酸和3-环戊基丙酸。
“杂烷基”指其中烃基团中的一个或一个以上碳原子被一个或一个以上下列基团取代的烷基:氨基、酰氨基、-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”指其中烃基团的一个或一个以上氢原子被一个或一个以上取代基取代的杂烷基,所述取代基选自卤素(即氟、氯、和 碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、用1-6个卤素取代的-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。
“烯基”指由两个或两个以上碳组成的烃基团,其中存在一个或一个以上碳碳双键。烯基烃基团可以是直链的或者包含一个或一个以上分支或环状基团。
“取代的烯基”指其中一个或一个以上氢被一个或一个以上取代基取代的烯基,所述的取代基选自卤素(即氟、氯、溴和碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、用1-6个卤素取代的-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”指具有至少一个带有共轭π-电子***的环的任选取代的芳香族基团,包含至多两个共轭的或稠合的环***。芳基包括但不限于羧芳基、杂环芳基和联芳基。优选地,芳基是5-或6-元环。优选的杂环芳基原子是一个或一个以上硫、氧和/或氮。芳基实例包括但不限于苯基、1-萘基、2-萘基、吲哚、喹啉、2-咪唑和9-蒽。芳基取代基选自-C1-20烷基、-C1-20烷氧基、卤素(即氟、氯、溴和碘)、-OH、-CN、-SH、-NH2、-NO2、用1-5个卤素取代的-C1-20烷基、-CF3、-OCF3和-(CH2)0-20-COOH。在不同的实施方案中,芳基包含0、1、2、3或4个取代基。
术语“卤代”包含氟代、氯代、溴代和碘代。
术语“(C1-C12)烃部分”包括烷基、烯基和炔基和在烯基和炔基的情况下为C2-C12。
“烷基芳基”指与“芳基”连接的“烷基”。
Glu(O-己基)是
Asp(1-庚醇)是
Glu(1-庚醇)是
Asp(NH-己基)是
Glu(NH-己基)是
Ser(正辛酰基)或Ser(C(O)-庚基)是
Dap(1-辛烷磺酰基)是
Cys(R15)是:
Cys(S-庚基)是
Dap(辛酰基)是
生物素基是
肉豆蔻基是
Lys(生物素基)是
Lys(肉豆蔻基)是
Gly(肉豆蔻基)是
本发明包括非对映异构体以及它们的外消旋和拆分的对映异构体纯的形式。生长素释放肽类似物可以包含D-氨基酸、L-氨基酸或其组合。优选地,生长素释放肽类似物中存在的氨基酸是L-对映异构体。
本发明类似物的优选衍生物包含D-氨基酸、N-烷基-氨基酸、β-氨基酸和/或一种或一种以上标记的氨基酸(包括标记形式的D-氨基酸、N-烷基-氨基酸或β-氨基酸)。标记的衍生物标明带有可检测标记物的氨基酸改变或者氨基酸衍生物。可检测标记物的实例包括发光标记物、酶标记物和放射性标记物。标记类型和标记位置均影响类似物活性。应该如此选择标记物并放置标记物以致于基本上不改变生长素释放肽类似物在GHS处的活性。特定标记物和位置对生长素释放肽活性的影响可以使用测定生长素释放肽活性和/或结合的分析法确定。
在C-末端羧基共价连接的保护基降低了体内条件下的羧基末端反应性。羧基末端保护基优选连接至最后一个氨基酸的α-羰基上。优选的羧基末端保护基包括酰胺、甲基酰胺和乙基酰胺。
本文所用的某些其它缩写定义如下:
名称和缩写
符号 含义
Boc:叔丁氧羰基
BSA:牛血清白蛋白
Bzl:苄基
DCM:二氯甲烷
DIC:N,N-二异丙基碳二亚胺
DIEA:二异丙基乙基胺
Dmab:4-{N-(1-(4,4-二甲基-2,6-二氧亚环己基)-3-甲基丁基)-氨基}苄基
DMAP:4-(二甲基氨基)吡啶
DMF:二甲基甲酰胺
DNP:2,4-二硝基苯基
EDTA 乙二胺四乙酸
Fmoc:芴基甲氧基羰基
HBTU:六氟磷酸2-(1H-苯并***-1-基)-1,1,3,3-四甲基脲鎓
cHex 环己基
HOAT:六氟磷酸O-(7-氮杂苯并***-1-基)-1,1,3,3-四甲基脲鎓
HOBt:1-羟基-苯并***
HPLC:高效液相色谱
MBHA4-甲基二苯甲基胺
Mmt:4-甲氧基三苯甲基
NMP:N-甲基吡咯烷酮
Pbf:2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基
PhiPrγ-2-苯基异丙酯
PyAOP:六氟磷酸7-氮杂苯并***-1-基氧基三(吡咯烷)鏻
tBu:叔丁基
TIS:三异丙基甲硅烷
TOS:甲苯磺酰基
trt三苯甲基
TFA:三氟乙酸
TFFH:四甲基氟代甲亚胺酸酰胺鎓六氟磷酸盐
Z:苯甲氧基羰基
合成方法
本发明的化合物可以使用本文实施例所公开的技术以及本领域众所周知的技术产生。例如生长素释放肽类似物的多肽区域可以化学合成或生物化学合成并修饰。用于涉及核酸向细胞内的导入以及核酸表达的生物化学合成的技术实例在Ausubel,Current Protocols in Molecular Biology,JohnWiley,1987-1998以及Sambrook等,Molecular Cloning,A LaboratoryManual,第二版,Cold Spring Harbor Laboratory Press,1989中提供。用于多肽化学合成的技术也是本领域众所周知的(Vincent in Peptide andProtein Drug Delivery,New York,N.Y.,Dekker,1990)。例如,本发明的肽可以通过标准固相肽合成制备(Stewart,J.M.等,Solid Phase Synthesis,Pierce Chemical Co.,第二版.1984)。
上面通式中的取代基R2和R3可以通过本领域已知的标准方法连接至N-末端氨基酸的游离胺上。例如,烷基如(C1-C30)烷基可以通过还原烷基化被连接。羟基烷基如(C1-C30)羟基烷基也可以通过还原烷基化连接,其中游离羟基用叔丁酯保护。酰基如COE1可以通过偶联游离酸如E1COOH与N-末端氨基酸的游离胺(通过将用3摩尔当量的游离酸完成的树脂和二氯甲烷中的二异丙基碳二亚胺混合1小时实现)连接。如果游离酸包含游离羟基,如对羟基苯基丙酸,则偶联应该用另外3摩尔当量的HOBT开展。
当R1是NH-X2-CH2-CONH2时(即Z0=CONH2),则肽的合成以偶联至Rink Amide-MBHA树脂(酰胺-4-甲基二苯甲基胺,得自于Novabiochem,San Diego,CA)的Fmoc-HN-X2-CH2-COOH开始。如果R1是NH-X2-CH2-COOH(即Z0-COOH),则肽的合成以偶联至Wang树脂的Fmoc-HN-X2-CH2-COOH开始。
在包含A5c、A6c和/或Aib的本发明生长素释放肽类似物的合成中,对于这些残基与紧跟其后的残基的偶联时间是2小时。
下面提供实施例以进一步说明本发明的不同特征。实施例还说明了用于开展本发明的有用的方法。这些实施例不限制所要求保护的发明。
实施例158:(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2(SEQ ID NO:118)
标题肽在Applied Biosystems433A型肽合成仪上(得自于AppliedBiosystems,Foster City,CA,U.S.A.)使用芴甲氧羰基(Fmoc)化学合成。采用具有0.64mmol/g取代的Rink Amide-4-甲基二苯甲基胺(MBHA)树脂(得自于Novabiochem,San Diego,CA)。使用的Fmoc氨基酸(得自于AnaSpec,San Jose,CA,U.S.A.)是Fmoc-Ala-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Aib-OH、Fmoc-Gln(Trt)-OH、Fmoc-Glu(tBu)-OH、Fmoc-His(Trt)-OH、Fmoc-Leu-OH、Fmoc-Lys(Boc)-OH、Fmoc-Phe-OH、Fmoc-Pro-OH、Fmoc-Ser(tBu)-OH和Fmoc-Val-OH。此外,对于第3和第17位氨基酸使用Fmoc-Glu(O-2-PhiPr)-OH(得自于Novabiochem,SanDiego,CA)。合成在0.1mmol规模上进行。通过用N-甲基吡咯烷酮(NMP)中的20%哌啶溶液处理树脂大约30分钟去除Fmoc基团。在每一偶联步骤中,Fmoc氨基酸(3eq,0.3mmol)首先在2mL NMP中的0.45M的六氟磷酸2-(1-H-苯并***-1-基)-1,1,2,3-四甲基脲鎓/1-羟基-苯并***(HBTU/HOBT)溶液中预活化。包含活化氨基酸酯的溶液与1mL二异丙基乙胺(DIEA)和1mL NMP一起加入到树脂中。将ABI 433A肽合成仪编程以执行下列反应循环:
(1)用NMP洗涤;
(2)用NMP中的20%哌啶去除Fmoc保护基30分钟;
(3)用NMP洗涤;和
(4)与预活化的Fmoc氨基酸偶联大约1或3小时。
按照标题肽的序列将树脂成功偶联。在肽链被装配后,树脂用N,N-二甲基甲酰胺(DMF)和二氯甲烷(DCM)充分洗涤。
在ABI 433A肽合成仪上装配肽链结束时(在A1上无Fmoc-Aib残基), 将肽-树脂转移至摇动器上的反应容器中,并且使用DMF中的25%哌啶去除Fmoc 30分钟。然后用DMF洗涤树脂。使用TFFH(四甲基氟代甲酰胺六氟磷酸盐)(得自于Perceptive Biosystems,Warrington,U.K.)(0.4毫摩尔)、HOAt(0.4mmol)、DMAP(二甲基氨基吡啶)(0.1g)和DIEA(1.2毫摩尔)将Fmoc-Aib-OH(0.4毫摩尔)偶联4小时一次并且偶联过夜一次。
如上述去除Fmoc基团并且使用DMF中的Ac2O(乙酸酐)(5毫摩尔)和DIEA(5毫摩尔)将肽封端大约30分钟。通过用DCM中的3%TFA溶液洗涤两次(每次洗涤10分钟)将PhiPr(γ-2-苯基异丙酯)基团从A3和A17谷氨酰胺残基上去除。通过使用DCM中的Boc2O(0.8毫摩尔)和DIEA(0.8毫摩尔)过夜替换从赖氨酸侧链部分去除的Boc。树脂用PyAOP(7-氮杂苯并***-1-基氧基三(吡咯烷)鏻六氟磷酸盐)(得自于AppliedBiosystems,Foster City,CA,U.S.A.)(0.6毫摩尔)、HOAt(0.6毫摩尔)、DMAP(0.1g)和DIEA(1.8毫摩尔)处理10分钟。然后将己基-NH2(己胺)(得自于Sigma-Aldrich Chemicals,St.Louis,MO,U.S.A.)(2.0毫摩尔)加入到树脂溶液中,将溶液摇动和静置过夜。
为了从树脂上切割下标题肽,肽-树脂用TFA、H2O和三异丙基甲硅烷(TIS)(分别为9.5mL/0.85mL/0.8mL)的混合物处理大约4小时。切割下的树脂被过滤去除,剩下的滤液注入到200mL***中。形成的沉淀通过离心收集。粗产物溶解于乙腈和水的混合物中,在带有C18 DYNAMAX-100A0 (得自于Varian,Walnut Creek,CA,U.S.A.)柱(4x43cm)的反相制备型HPLC***上纯化。使用在大约1小时从85%A∶15%B至60%A∶40%B的线性梯度洗脱柱,其中A是水中的0.1%TFA,B是乙腈中的0.1%TFA。通过HPLC分析级分,并且将包含纯产物的那些级分混合并冷冻至干。回收得到大约27.1mg(6.3%)的白色固体,经HPLC分析发现纯度大约为97.5%。电喷射电离质谱(ESI-MS)分析确定分子量为3477.4,这与理论分子量3477.19一致。
实施例70:(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2 (SEQ ID NO:50)
根据描述用于实施例158,即(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2)的方法合成标题肽,具有如下例外:在摇动器上偶联第1位上的最末Fmoc-Aib-OH之后,通过用DCM中的3%TFA以大约10分钟的间隔洗涤两次将PhiPr保护基从A3和A17谷氨酰胺残基上去除。使用DCM中的Boc2O(0.8毫摩尔)和DIEA(0.8毫摩尔)溶液置换从赖氨酸侧链部分去除的Boc。在摇动和静置过夜后,树脂用PyAOP(7-氮杂苯并***-1-基氧基三(吡咯烷)鏻六氟磷酸盐)(得自于AppliedBiosystems,Foster City,CA,U.S.A.)(0.6毫摩尔)、HOAt(0.6毫摩尔)、DMAP(0.1g)和DIEA(1.8毫摩尔)溶液处理10分钟,之后将己基-NH2(己胺)(得自于Sigma-Aldrich,St.Louis,MO,U.S.A.)(2.0毫摩尔)加入到溶液中,将溶液摇动并静置过夜。然后使用DMF中的25%哌啶去除Fmoc保护基。如在上面实施例158合成中所详细讨论,将肽从树脂上切割下来并在HPLC***上纯化。
使用HPLC分析法,发现所得到产物的纯度为大约96.5%。电喷射电离质谱(ESI-MS)分析确定的分子量为3435.00,其与理论分子量3435.16一致。
下列本发明的肽可以由本领域普通技术人员使用类似于上面一般性公开方法的合成方法来制备:
实施例1:(Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:1)
实施例2:(Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:2)
实施例3:(Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:3)
实施例4:(Glu(NH-己基)3,Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:4)
实施例5:(Aib2,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ IDNO:5)
实施例6:(Aib2,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:6)
实施例7:(Aib2,8,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID
NO:7)
实施例8:(Aib2,8,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQID NO:8)
实施例9:(Aib2,10,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQID NO:9)
实施例10:(Aib2,10,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQID NO:10)
实施例11:(Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:11)
实施例12:(Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:12)
实施例13:(Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:13)
实施例14:(Glu(NH-己基)3,Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:14)
实施例15:(Aib2,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ IDNO:15)
实施例16:(Aib2,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQID NO:16)
实施例17:(Aib2,8,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQID NO:17)
实施例18:(Aib2,8,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQID NO:18)
实施例19:(Aib2,10,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQID NO:19)
实施例20:(Aib2,10,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:20)
实施例21:(Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:21)
实施例22:(Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:22)
实施例23:(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:23)
实施例24:(Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:24)
实施例25:(Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:25)
实施例26:(Dap(辛烷磺酰基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:26)
实施例27:(Dap(辛烷磺酰基)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:27)
实施例28:(Dap(辛烷磺酰基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:28)
实施例29:(Glu(NH-己基)3,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:29)
实施例30:(Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:30)
实施例31:(Cys(S-(CH2)9CH3)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:31)
实施例32:(Glu(NH-己基)3,Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:32)
实施例33:(Cys(S-(CH2)9CH3)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:33)
实施例34:(Cys(S-(CH2)9CH3)3,Ser(正辛酰基)17)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:34)
实施例35:(Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:35)
实施例36:(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:36)
实施例37:(Aib2,Thz7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:37)
实施例38:(Aib2,4-Hyp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:37)
实施例39:(Aib2,Dhp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:37)
实施例40:(Aib2,Pip7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:37)
实施例41:(Aib2,Tic7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:37)
实施例42:(Aib2,Glu(NH-己基)3,17,Thz7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:38)
实施例43:(Aib2,Glu(NH-己基)3,17,4-Hyp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:38)
实施例44:(Aib2,Glu(NH-己基)3,17,Dhp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:38)
实施例45:(Aib2,Glu(NH-己基)3,17,Pip7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:38)
实施例46:(Aib2,Glu(NH-己基)3,17,Tic7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:38)
实施例47:(Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:39)
实施例48:(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
实施例49:(Aib2,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:41)
实施例50:(Aib2,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:41)
实施例51:(Aib2,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:41)
实施例52:(Aib2,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:41)
实施例53:(Aib2,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:42)
实施例54:(Aib2,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:42)
实施例55:(Aib2,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:42)
实施例56:(Aib2,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:42)
实施例57:(Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:43)
实施例58:(Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:44)
实施例59:(Aib8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:45)
实施例60:(Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:46)
实施例61:(3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:46)
实施例62:(4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:46)
实施例63:(2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:46)
实施例64:(Glu(NH-己基)3,17,Aib8)h生长素释放肽(1-28)-NH2;(SEQID NO:47)
实施例65:(Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQID NO:48)
实施例66:(Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQID NO:48)
实施例67:(Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQID NO:48)
实施例68:(Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQID NO:48)
实施例69:(Aib1,2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:49)
实施例71:(A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:51)
实施例72:(A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:52)
实施例73:(Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:53)
实施例74:(Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:54)
实施例75:(Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:55)
实施例76:(Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:56)
实施例77:(Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:57)
实施例78:(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:58)
实施例79:(Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:59)
实施例80:(Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:60)
实施例81:(Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:61)
实施例82:(Glu(NH-己基)3,Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:62)
实施例83:(Aib2,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ IDNO:63)
实施例84:(Aib2,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQID NO:64)
实施例85:(Aib2,8,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQID NO:65)
实施例86:(Aib2,8,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQID NO:66)
实施例87:(Aib2,10,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQID NO:67)
实施例88:(Aib2,10,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQID NO:68)
实施例89:(Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:69)
实施例90:(Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:70)
实施例91:(Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:71)
实施例92:(Glu(NH-己基)3,Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:72)
实施例93:(Aib2,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ IDNO:73)
实施例94:(Aib2,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQID NO:74)
实施例95:(Aib2,8,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQID NO:75)
实施例96:(Aib2,8,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQID NO:76)
实施例97:(Aib2,10,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQID NO:77)
实施例98:(Aib2,10,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQID NO:78)
实施例99:(Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:79)
实施例100:(Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:80)
实施例101:(Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ IDNO:81)
实施例102:(Glu(NH-己基)3,Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:82)
实施例103:(Aib2,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQID NO:83)
实施例104:(Aib2,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQID NO:84)
实施例105:(Aib2,8,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:85)
实施例106:(Aib2,8,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQID NO:86)
实施例107:(Aib2,10,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQID NO:87)
实施例108:(Aib2,10,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:88)
实施例109:(Ac-Gly1,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:89)
实施例110:(Ac-Gly1,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:90)
实施例111:(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:91)
实施例112:(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:92)
实施例113:(Ac-Gly1,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:93)
实施例114:(Ac-Gly1,Dap(辛烷磺酰基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:94)
实施例115:(Ac-Gly1,Dap(辛烷磺酰基)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:95)
实施例116:(Ac-Gly1,Dap(辛烷磺酰基)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:96)
实施例117:(Ac-Gly1,Glu(NH-己基)3,Dap(辛烷磺酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:97)
实施例118:(Ac-Gly1,(Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SID NO:98)
实施例119:(Ac-Gly1,(Cys(S-(CH2)9CH3)3,17)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:99)
实施例120:(Ac-Gly1,Glu(NH-己基)3,(Cys(S-(CH2)9CH3)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:100)
实施例121:(Ac-Gly1,(Cys(S-(CH2)9CH3)3,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:101)
实施例122:(Ac-Gly1,(Cys(S-(CH2)9CH3)3,Ser(正辛酰基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:102)
实施例123:(Ac-Gly1,Aib2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:103)
实施例124:(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:104)
实施例125:(Ac-Gly1,Aib2,Thz7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
实施例126:(Ac-Gly1,Aib2,4-Hyp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
实施例127:(Ac-Gly1,Aib2,Dhp7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
实施例128:(Ac-Gly1,Aib2,Pip7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
实施例129:(Ac-Gly1,Aib2,Tic7,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:105)
实施例130:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Thz7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
实施例131:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,4-Hyp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
实施例132:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Dhp7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
实施例133:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Pip7)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:106)
实施例134:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Tic7)h生长素释放肽(1-28)-NH2;(SEQ ID NO:106)
实施例135:(Ac-Gly1,Aib2,8,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:107)
实施例136:(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:108)
实施例137:(Ac-Gly1,Aib2,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
实施例138:(Ac-Gly1,Aib2,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
实施例139:(Ac-Gly1,Aib2,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
实施例140:(Ac-Gly1,Aib2,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:109)
实施例141:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
实施例142:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
实施例143:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
实施例144:(Ac-Gly1,Aib2,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:110)
实施例145:(Ac-Gly1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:111)
实施例146:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:112)
实施例147:(Ac-Gly1,Aib8,Glu(NH-己基)17)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:113)
实施例148:(Ac-Gly1,Taz9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:114)
实施例149:(Ac-Gly1,3-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:114)
实施例150:(Ac-Gly1,4-Pal9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:114)
实施例151:(Ac-Gly1,2-Thi9,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:114)
实施例152:(Ac-Gly1,Glu(NH-己基)3,17,Aib8)h生长素释放肽(1-28)-NH2;(SEQ ID NO:115)
实施例153:(Ac-Gly1,Glu(NH-己基)3,17,Taz9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:116)
实施例154:(Ac-Gly1,Glu(NH-己基)3,17,3-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:116)
实施例155:(Ac-Gly1,Glu(NH-己基)3,17,4-Pal9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:116)
实施例156:(Ac-Gly1,Glu(NH-己基)3,17,2-Thi9)h生长素释放肽(1-28)-NH2;(SEQ ID NO:116)
实施例157:(Ac-Aib1,Aib2,10,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:117)
实施例159:(Ac-Gly1,A5c2,Glu(NH-己基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:119)
实施例160:(Ac-Gly1,A5c2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:120)
实施例161:(Ac-Gly1,Glu(1-庚醇)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:121)
实施例162:(Ac-Gly1,Asp(1-庚醇)3,17)h生长素释放肽(1-28)-NH2; (SEQ ID NO:122)
实施例163:(Ac-Gly1,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:123)
实施例164:(Ac-Gly1,Asp(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:124)
实施例165:(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:125)
实施例166:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:126)
实施例167:(Ac-Gly1,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:127)
实施例168:(Ac-Gly1,Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:128)
实施例169:(Ac-Gly1,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:129)
实施例170:(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:130)
实施例171:(Ac-Gly1,Aib2,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:131)
实施例172:(Ac-Gly1,Aib2,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:1312)
实施例173:(Ac-Gly1,Aib2,8,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:133)
实施例174:(Ac-Gly1,Aib2,8,Glu(NH-己基)3,15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:134)
实施例175:(Ac-Gly1,Aib2,10,Glu(NH-己基)15)h生长素释放肽(1-28)-NH2;(SEQ ID NO:135)
实施例176:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,15)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:136)
实施例177:(Ac-Gly1,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:137)
实施例178:(Ac-Gly1,Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:138)
实施例179:(Ac-Gly1,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:139)
实施例180:(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:140)
实施例181:(Ac-Gly1,Aib2,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:141)
实施例182:(Ac-Gly1,Aib2,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:142)
实施例183:(Ac-Gly1,Aib2,8,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:143)
实施例184:(Ac-Gly1,Aib2,8,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:144)
实施例185:(Ac-Gly1,Aib2,10,Glu(NH-己基)16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:145)
实施例186:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,16)h生长素释放肽(1-28)-NH2;(SEQ ID NO:146)
实施例187:(Ac-Gly1,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:147)
实施例188:(Ac-Gly1,Ser(正辛酰基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:148)
实施例189:(Ac-Gly1,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:149)
实施例190:(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)18)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:150)
实施例191:(Ac-Gly1,Aib2,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:151)
实施例192:(Ac-Gly1,Aib2,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:152)
实施例193:(Ac-Gly1,Aib2,8,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:153)
实施例194:(Ac-Gly1,Aib2,8,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:154)
实施例195:(Ac-Gly1,Aib2,10,Glu(NH-己基)18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:155)
实施例196:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,18)h生长素释放肽(1-28)-NH2;(SEQ ID NO:156)
实施例197:(Ac-Gly1,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:157)
实施例198:(Ac-Gly1,Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:158)
实施例199:(Ac-Gly1,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:159)
实施例200:(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:160)
实施例201:(Ac-Gly1,Aib2,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:161)
实施例202:(Ac-Gly1,Aib2,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:162)
实施例203:(Ac-Gly1,Aib2,8,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:163)
实施例204:(Ac-Gly1,Aib2,8,Glu(NH-己基)3,19)h生长素释放肽 (1-28)-NH2;(SEQ ID NO:164)
实施例205:(Ac-Gly1,Aib2,10,Glu(NH-己基)19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:165)
实施例206:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,19)h生长素释放肽(1-28)-NH2;(SEQ ID NO:166)
实施例207:(Ac-Gly1,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:167)
实施例208:(Ac-Gly1,Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:168)
实施例209:(Ac-Gly1,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:169)
实施例210:(Ac-Gly1,Glu(NH-己基)3,Ser(正辛酰基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:170)
实施例211:(Ac-Gly1,Aib2,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:171)
实施例212:(Ac-Gly1,Aib2,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:172)
实施例213:(Ac-Gly1,Aib2,8,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:173)
实施例214:(Ac-Gly1,Aib2,8,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:174)
实施例215:(Ac-Gly1,Aib2,10,Glu(NH-己基)20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:175)和
实施例216:(Ac-Gly1,Aib2,10,Glu(NH-己基)3,20)h生长素释放肽(1-28)-NH2;(SEQ ID NO:176)
实施例217:(Aib2,Lys(肉豆蔻基)17)h生长素释放肽(1-28)-NH2;(SEQID NO:177)和
实施例218:(Gly(肉豆蔻基)1,Aib2,Lys(肉豆蔻基)17)h生长素释放肽 (1-28)-NH2.(SEQ ID NO:178)
一组上面所列优选实施方案通过电喷射电离质谱(ESI-MS)分析以确定分子量。下表1是该测试过程中汇总的数据。通过HPLC所分析的每一个所选择化合物的纯度也提供在表1A、1B和1C中。
表1A-所选择化合物的分子量和纯度
实施例# | 化合物 | 分子量 (理论的) | 分子量 (MS-ES) | 纯度 (%) |
#48 (SEQ ID NO:40) | (Aib2,8,Glu(NH-己基)3,17)h 生长素释放肽(1-28)-NH2 | 3406.12 | 3405.70 | 99.9% |
#136 (SEQ ID NO:108) | (Ac-Gly1,Aib2,8,Glu(NH-己 基)3,17)h生长素释放肽 (1-28)-NH2 | 3448.16 | 3447.98 | 98.0% |
#124 (SEQ ID NO:104) | (Ac-Gly1,Aib2,Glu(NH-己 基)3,17)h生长素释放肽 (1-28)-NH2 | 3492.17 | 3492.00 | 99.0% |
实施例# | 化合物 | 分子量 (理论的) | 分子量 (MS-ES) | 纯度 (%) |
#166 (SEQ ID NO:126) | (Ac-Gly1,Aib2,10Glu(NH-己 基)3,Lys(生物素基)17)h生长 素释放肽(1-28)-NH2 | 3591.32 | 3591.50 | 98.4% |
#70 (SEQ ID NO:50) | (Aib1,2,10,Glu(NH-己基)3,17)h 生长素释放肽(1-28)-NH2 | 3435.16 | 3435.00 | 96.5% |
#158 (SEQ ID NO:118) | (Ac-Aib1,Aib2,10,Glu(NH-己 基)3,17)h生长素释放肽 (1-28)-NH2 | 3477.19 | 3477.40 | 97.5% |
#146 (SEQ ID NO:112) | (Ac-Gly1,Aib2,10,Glu(NH-己 基)3,17)h生长素释放肽 (1-28)-NH2 | 3449.14 | 3449.20 | 99.0% |
#78 (SEQ ID NO:58) | (Lys(生物素基)17)h生长素释 放肽(1-28)-NH2 | 3595.27 | 3594.90 | 97.7% |
表1B-所选择化合物的分子量和纯度
实施例# | 化合物 | 分子量 (理论的) | 分子量 (MS-ES) | 纯度 (%) |
#217 (SEQ ID NO:177) | (Aib2,Lys(肉豆蔻基)17)h生 长素释放肽(1-28)-NH2 | 3577.35 | 3577.2 | 99.2% |
#218 (SEQ ID NO:178) | (Gly(肉豆蔻基)1,Aib2, Lys(肉豆蔻基)17)h生长素释 放肽(1-28)-NH2 | 3787.71 | 3788.2 | 98.6% |
表1C-所选择化合物的分子量和纯度
实施例# | 化合物 | 分子量 (理论的) | 分子量 (MS-ES) | 纯度 (%) |
#58 (SEQ ID NO:44) | (Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2 | 3407.10 | 3407.20 | 100% |
生物学活性测定
GHS受体结合测定分析
本发明化合物在GHS受体处的活性可以使用如在下面所提供实施例中描述的那些技术确定。在不同的实施方案中,生长素释放肽类似物相对于生长素释放肽具有至少大约50%、至少大约60%、至少大约70%、至少大约80%、至少大约90%、至少大约95%、至少大约98%或更多的功能活性(如通过使用一种或一种以上下述功能活性分析法所测定);和/或具有大于约1000nM、大于约100nM或、大于约50nM的IC50(使用下述的受体结合分析法)。关于IC50,更大值意味着更有效,并因此表明对于实现结合抑制需要更少的量。
测定化合物与GHS受体结合能力的分析法采用GHS受体、包含生长素释放肽结合位点的受体片段、包含此片段的多肽或多肽的衍生物。优选地,分析法使用GHS受体或其片段。
包含结合生长素释放肽的GHS受体片段的多肽还可以包含GHS受体中不存在的一个或一个以上多肽区。此多肽的衍生物包含结合生长素释放肽的GHS受体片段和一个或一个以上非肽成分。
参与生长素释放肽结合的GHS受体氨基酸序列可以使用标记的生长素释放肽或生长素释放肽类似物和不同的受体片段容易地鉴定。可以采用不同的策略以选择待测试的片段,从而缩小结合区的范围。此类策略实例包括但不限于测试从N-末端开始的15个氨基酸长度的连续片段和测试更长的片段。如果测试更长的片段,则结合生长素释放肽的片段可以被细分以进一步定位生长素释放肽结合区域。用于结合研究的片段可以使用重组核酸技术产生。
结合分析法可以使用各个化合物或包含不同数量化合物的制备物开展。包含能够结合GHS受体的不同数量化合物的制备物可以分成更小的组,以便测试鉴定结合GHS受体的一种或多种化合物。在本发明的一个实施方案中,在结合分析法中使用包含至少10种化合物的测试制备物。
结合分析法可以使用存在于不同环境下的重组产生的GHS受体多肽开展。此类环境包括例如包含从重组核酸或天然存在核酸所表达GHS受体多肽的细胞提取物和纯化的细胞提取物;并且也包括例如使用引入到不同环境中的通过重组方式或者从天然存在核酸所产生的纯化GHS受体多肽。
GHS受体活性化合物的筛选
使用重组表达的受体方便对GHS受体活性化合物的筛选。重组表达的GHS受体赋予几个优点,例如能够在确定的细胞***中表达受体以致于在GHS受体处对化合物的反应可以更容易地与在其它受体处的反应区别开来。例如,通过表达载体,GHS受体可以在通常不表达受体的细胞系,例如HEK 293、COS 7和CHO中表达,其中不包含表达载体的同一细胞系用作对照。
在提供GHS受体活性的分析法中使用生长素释放肽类似物利于筛选降低CHS受体活性的化合物。可以测量测试化合物对此类活性的影响以鉴定例如变构效应调节物和拮抗剂。
GHS受体活性可以使用不同的技术测定,例如检测GHS受体的细胞内构象的改变、G蛋白偶联活性的改变和/或细胞内信使的改变。优选地,GHS受体活性可使用技术如测定细胞内Ca2+的那些技术测定。可以采用测定Ca2+的本领域众所周知的技术实例包括使用染料如Fura-2和使用Ca2+-生物发光敏感报告蛋白质如水母发光蛋白。采用水母发光蛋白测定G蛋白活性的细胞系的实例是HEK293/aeq17(Button,D.等,Cell Calcium,(1993),14(9):663-71;以及Feighner,S.D.等,Science,(1999),284(5423):2184-8)。
功能性偶联至不同G蛋白的包含生长素释放肽结合区域的嵌合受体也可用于测定GHS受体活性。嵌合GHS受体包含N-末端细胞外结构域、构成跨膜区的跨膜结构域、细胞外环区和细胞内环区和细胞内羧基末端。产生嵌合受体和测量G蛋白偶联反应的技术在例如国际专利申请号PCT/US96/12336[WO 97/05252]和美国专利5,264,565(在此引入作为参考) 中提供。
GHS受体活性的刺激
生长素释放肽类似物可用于刺激GHS受体活性,这可用于例如研究GHS受体调节和/或GH分泌的效应、鉴定生长素释放肽拮抗剂和/或使患有如GH缺乏状态、肌肉质量和/或骨密度降低、性功能障碍、非健康体重、运动技能和/或身体机能丧失和/或缺乏正常食欲的疾病或状况的受试者受益。
在易受体重减轻影响的个体中,如患病个体或老年个体中维持理想的、健康的体重的关键是增加体重或食欲。在体重不足的受试者中体重或食欲的损失会导致严重的健康问题。在患病或者经历导致体重减轻和/或正常食欲缺乏的医学治疗的患者中,所述疾病或状况的治疗效果视患者维持一致体重的能力而定。体重不足的受试者包括体重比“正常”体重范围的下限或体重指数(“BMI”)低约10%或更少、20%或更少或30%或更少的那些受试者,其中体重指数是通过计算以千克计的体重除以以米计的身高的平方来确定的。在本领域众所周知,BMI的“正常”范围是19-22。体重指数低于“正常”范围的那些个体对疾病更易感,并且某些有益的医学治疗如化学疗法在具有亚正常BMI的个体中效果更差。
生物学分析法-实施例
1.受体结合分析法
A.表达人重组GHS受体的CHO-K1细胞的制备
使用本领域技术人员众所周知的聚合酶链式反应(PCR)技术克隆人GH促分泌素受体(hGHS-R或生长素释放肽受体)的cDNA,其中使用作为模板的人脑RNA(得自于Clontech,Palo Alto,CA,U.S.A.)、位于hGHS-R全长编码序列两侧的基因特异性引物(S:5′-ATGTGGAACGCGACGCCCAGCGAAGAG-3′和AS:5′-TCATGTATTAATACTAGATTCTGTCCA-3′)以及Advantage 2 PCR Kit(可从Clontech,Palo Alto,CA,U.S.A.得到)。使用Original TA Cloning Kit(得 自于Invitrogen,Carlsbad,CA,U.S.A.)将PCR产物克隆入pCR2.1载体。将全长人GHS-R亚克隆入哺乳动物表达载体pcDNA 3.1中(可从Invitrogen,Carlsbad,CA,U.S.A.得到)。使用如在Wigler,M.等,Cell,(1977),11(1):223-32中描述的已知的磷酸钙方法,将质粒转染进入中国仓鼠卵巢细胞系CHO-K1中(由美国典型培养物保藏中心(American TypeCulture Collection,Rockville,MD,U.S.A.)提供)。通过在补加10%胎牛血清和1mM丙酮酸钠并含有0.8mg/ml G418(从Gibco,Grand Island,NY,U.S.A.购买)的RPMI 1640培养基中选择在克隆环中生长的已转染细胞得到稳定表达hGHS-R的单细胞克隆。
B.GHS-R结合分析法:
用于放射配体结合研究的膜可如下制备:用Brinkman Polytron(Brinkman,Westbury,NY,U.S.A.)将表达人重组GHS受体的上述CHO-K1细胞在大约20ml冰预冷的50mM Tris-HCl中以设定6匀浆大约15秒。通过离心(39,000g/10分钟)洗涤匀浆物两次,并且最后的沉淀重悬于包含2.5mM MgCl2和0.1%牛血清白蛋白(BSA)的大约50mMTris-HCl中。对于所选择的分析法,将大约0.4ml的等分试样与0.05nM(125I)生长素释放肽(~2000Ci/mmol;Perkin Elmer Life Sciences,Boston,MA,U.S.A.)以及与或不与0.05ml未标记的竞争测试肽温育。在4℃大约60分钟后,通过经GF/C滤器(可从Brandel,Gaithersburg,MD,U.S.A.得到)快速过滤将结合的(125I)生长素释放肽与游离的生长素释放肽分离,其中滤器预先浸渍于0.5%聚乙烯亚胺/0.1%BSA中。然后用5ml冰预冷的50mM Tris-HCl和0.1%BSA洗涤滤器三次。在滤器上截留的结合放射性通过γ射线分光法计数(使用来自Wallace LKB,Gaithersburg,MD,U.S.A.的分光计)。通过从结合的总(125I)生长素释放肽中减去在1000nM生长素释放肽(可从Bachem,Torrence,CA,U.S.A.得到)存在下结合的(125I)生长素释放肽,确定特异性结合。
使用上面讨论的受体结合分析法测试选择的优选实施方案并且结果报 道于下表2中。
表2-所选择化合物的受体结合Ki值
实施例# | 化合物 | Ki(nM) |
#48 (SEQ ID NO:40) | (Aib2,8,Glu(NH-己基)3,17)h生长素释放肽 (1-28)-NH2 | 0.45 |
#136 (SEQ ID NO:108) | (Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释 放肽(1-28)-NH2 | 2.94 |
#124 (SEQ ID NO:104) | (Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放 肽(1-28)-NH2 | 1.68 |
#166 (SEQ ID NO:126) | (Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素 基)17)h生长素释放肽(1-28)-NH2 | 1.28 |
#70 (SEQ ID NO:50) | (Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽 (1-28)-NH2 | 0.63 |
实施例# | 化合物 | Ki(nM) |
#158 (SEQ ID NO:118) | (Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释 放肽(1-28)-NH2 | 24.44 |
#146 (SEQ ID NO:112) | (Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释 放肽(1-28)-NH2 | 0.99 |
#78 (SEQ ID NO:58) | (Lys(生物素基)17)h生长素释放肽(1-28)-NH2 | 0.07 |
2.GHS-R功能活性分析法
A.体外GSH受体介导的细胞内iCa2+动员
通过在0.3%EDTA/磷酸缓冲盐溶液中于25℃温育,收获表达人GSH受体的上述CHO-K1细胞;然后通过离心将细胞洗涤2次。经洗涤的细胞重悬于Hank缓冲盐溶液中(HBSS)用于装载荧光Ca2+指示剂Fura-2AM。大约106个细胞/ml的细胞悬浮液与2μM Fura-2AM于大约25℃温育约30分钟。通过在HBSS离心两次去除未装载的Fura-2AM,并且将最后的悬浮液转移至分光荧光计(型号Hitachi F-2000Tokyo,日本),该分光荧光计配备有磁力搅拌机械装置和温度调节的比色杯架。在平衡至37℃后,加入生长素释放肽类似物以测量细胞内Ca2+动员。激发波长和发射波长分别是340和510nm。使用该分析方法发现实施例124和136化合物在生长素释放肽受体处具有拮抗活性。
B.体内GH释放/抑制
如本领域众所周知,可以测试化合物体内刺激或抑制GH释放的能力。(Deghenghi,R.等,Life Sciences,(1994),54(18):1321-8;以及国际专利申请号PCT/EP01/07929[WO 02/08250])。为了确定化合物体内刺激GH释放的能力,将所选择的化合物以约300mg/kg的剂量皮下注射入10-日龄大鼠中。在注射后大约15分钟测量循环的GH,并与用溶剂对照注射的大鼠中的GH水平相比。
类似地,可以测试所选择化合物体内拮抗生长素释放肽所诱导GH分泌的能力。300mg/kg剂量的本申请的化合物与生长素释放肽一同皮下注射入10-日龄大鼠中。在注射大约15分钟后测量循环的GH,并且与仅用生长素释放肽注射的大鼠中的GH水平相比。
施用
可使用本文提供的指导以及本领域众所周知的技术将生长素释放肽类似物配制并施用于受试者。优选的施用途径保证有效量的化合物达到靶点。药物施用的指导大体在例如Remington′s Pharmaceutical Sciences第18版,Gennaro编,Mack Publishing,1990以及Modem Pharmaceutics第二版,Banker和Rhodes编,Marcel Dekker,Inc.,1990中提供,该两篇文献在此引入作为参考。
生长素释放肽类似物可制备成酸性盐或碱性盐。可药用盐(以水或油可溶或可分散产物的形式)包括从无机或有机酸或碱形成的常规无毒性盐或季铵盐。此类盐的实例包括但不限于酸加成盐,例如乙酸盐、己二酸盐、海藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、 果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐;以及碱盐,如铵盐、碱金属盐如钠和钾盐、碱土金属盐如钙盐和镁盐、与有机碱形成的盐如二环己基胺盐、N-甲基-D-葡萄糖胺以及与氨基酸如精氨酸和赖氨酸形成的盐。
生长素释放肽类似物可以使用不同的途径施用,包括口服和经鼻摄入或通过经皮注射和经粘膜注射。作为混悬剂口服施用的活性成分可以根据药物制剂领域众所周知的技术制备,并且可以包含用于增加体积的微晶纤维素、作为悬浮剂的海藻酸或海藻酸钠、作为增粘剂的甲基纤维素和甜味剂/调味剂。作为立即释放的片剂,药物制剂可以包含微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和乳糖和/或其它赋形剂、粘合剂、膨胀剂、崩解剂、稀释剂和润滑剂。
经鼻气雾剂或吸入制剂的施用可以配制成,例如盐水中的溶液,其使用苄基醇或其它适宜防腐剂、增强生物利用度的吸收促进剂、使用氟碳化合物和/或使用其它增溶剂或分散剂。
生长素释放肽类似物可以静脉内施用(推注和输注)、腹膜内施用、皮下施用、局部施用(包藏或不包藏)或肌内施用。当通过注射施用时,可使用适宜的非毒性的、肠胃外可接受的稀释剂或溶剂(如林格液或等渗氯化钠溶液)或者适宜的分散剂或润湿剂和悬浮剂(如无菌温和的不挥发油,包括合成的甘油一酯或甘油二酯和包括油酸在内的脂肪酸)配制注射溶液或混悬液。
适宜的剂量方案优选考虑本领域众所周知的因素来确定,所述因素包括待给药的受试者类型;受试者的年龄、体重、性别和医学状况;施用途径;受试者的肾功能和肝功能;预期效果;以及所采用的具体化合物。
实现在药物范围内有效却无毒性的药物浓度的最佳精度需要基于靶位点药物利用度动力学的方案。这包括考虑药物的分布、平衡和清除。受试者的每日剂量预期为每个受试者每天0.01和1000mg之间。
生长素释放肽类似物可以在药盒中提供。此药盒一般包含用于施用的 剂量形式的活性化合物。剂量形式包含足够量的活性化合物,以致于在1天或1天以上的时间过程中以规则间隔(如一天1-6次)向受试者施用时,可以得到预期的效果。优选地,药盒包含说明书,其标明剂量形式的使用以实现预期效果以及在指定的时间段内接收的剂量形式的量。
本发明已经以例证方式进行了描述,并且应当理解所使用的术语旨在处于描述用措辞的本质之内,而非对其的限制。显而易见,根据上述教导,可能存在本发明的许多修改和变型。因此,应当理解,本发明可以在后附权利要求范围之内实施,而不是按照所具体描述的实施。
在此引用的专利和科学文献代表着本领域技术人员可以得到的知识。所有专利、专利公布和本文引用的其它出版物在此全文引入作为参考。
Claims (2)
1.化合物或其可药用盐,其中所述化合物是:
(Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:40)
(Ac-Gly1,Aib2,8,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:108)
(Ac-Gly1,Aib2,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:104)
(Aib1,2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQ IDNO:50)
(Ac-Aib1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:118)或
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,17)h生长素释放肽(1-28)-NH2;(SEQID NO:112)。
2.化合物或其可药用盐,其中所述化合物是:
(Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:58)或
(Ac-Gly1,Aib2,10,Glu(NH-己基)3,Lys(生物素基)17)h生长素释放肽(1-28)-NH2;(SEQ ID NO:126)。
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2006
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- 2006-09-27 CN CN201510520759.7A patent/CN105111302A/zh active Pending
- 2006-09-27 EP EP06825217.0A patent/EP1928489B1/en active Active
- 2006-09-27 JP JP2008533604A patent/JP4896140B2/ja not_active Expired - Fee Related
- 2006-09-27 WO PCT/US2006/037889 patent/WO2007038678A2/en active Application Filing
- 2006-09-27 ES ES06825217.0T patent/ES2474643T3/es active Active
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2008
- 2008-03-28 US US12/079,885 patent/US8258094B2/en active Active
- 2008-06-26 HK HK08107092.4A patent/HK1112580A1/zh not_active IP Right Cessation
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2011
- 2011-10-11 JP JP2011224117A patent/JP2012072144A/ja active Pending
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Also Published As
Publication number | Publication date |
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US8258094B2 (en) | 2012-09-04 |
JP4896140B2 (ja) | 2012-03-14 |
JP2012072144A (ja) | 2012-04-12 |
CA2625920C (en) | 2014-12-23 |
CN101282738A (zh) | 2008-10-08 |
US20090156483A1 (en) | 2009-06-18 |
HK1112580A1 (zh) | 2008-09-12 |
CN105111302A (zh) | 2015-12-02 |
WO2007038678A8 (en) | 2008-06-19 |
CA2625920A1 (en) | 2007-04-05 |
WO2007038678A2 (en) | 2007-04-05 |
ES2474643T3 (es) | 2014-07-09 |
EP1928489B1 (en) | 2014-03-26 |
JP2009510088A (ja) | 2009-03-12 |
EP1928489A2 (en) | 2008-06-11 |
EP1928489A4 (en) | 2009-11-11 |
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