CN101432294B - 类似于生长激素的肽性促分泌素的化合物以及包含其的制剂及用途 - Google Patents
类似于生长激素的肽性促分泌素的化合物以及包含其的制剂及用途 Download PDFInfo
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Abstract
通过计算机分子建模获得的肽化合物，它的结构使得其能够执行与生长激素肽性促分泌素相同的功能。本发明还包括包含所述化合物的制剂，以及其在制备用于人或动物使用的药剂、营养补充剂或者其他制剂中的用途。
Description
技术领域
本发明属于调节生物体的代谢活性和细胞保护作用的生物学活性分子实体的合理设计领域。更具体而言，涉及类似于生长激素的肽性促分泌素的化合物，其活性包括但不限于：生长激素的受控释放、心脏保护、心血管系统的功能应答的提高、神经保护、食欲的控制和调节、脂肪摄入和能量代谢。
现有技术
生长激素(GH)的合成促分泌素属于包括肽性和非肽性分子的配体家族。这些首先的合成分子是在分离出生长激素释放激素(GrowthHormone Releasing Hormone，GHRH)之前由Momany和Bowers设计出的肽。已开发了6和7个氨基酸残基的合成肽(生长激素释放肽(Growth Hormone Releasing Peptide，GHRP))，其产生有效的GH释放；此类肽在了解其在生物体中的功能或其作用方式前得到了描述。突变研究以及体内和体外实验揭示出，由充当间隔物的一个氨基酸分开的2个氨基酸L-D和D-L的排列(没有丧失原始构象)被认为对于GH释放活性是最佳的，并且定型出了肽(His-D-Trp-Ala-D-Trp-Phe-NH2)，其以10-30ng/mL的浓度释放GH，达到称为GHRP-6的肽(His-D-Trp-Ala-Trp-D-Phe-Lys-NH2)，其中Lys残基仅是改善体内活性所需的，因为据信它在体外无功能(Momany F.A.，Bowers C.Y.等人(1981)Design，synthesis andbiologic alactivity of peptides which release growth hormone， in vitro.Endocrinology，108：31-39)。
发现了其他类似肽；在1993年，Bowers等人发现了2种GHRP-6类似肽：GHRP-2(D-Ala-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2)和GHRP-1(Ala-His-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2)。这3种促分泌素在体外显示出从温育的下丘脑-垂体中比从单独的垂体中释放出更多的GH，这证实下丘脑冲动(impulse)在此类作用中是重要的，还证实即使在人中GHRP和GHRH的协同作用也比两者中的任何一种本身释放出更多的GH(BowersC.Y.(1993)GH-releasing peptides：structureand kinetics.J Pediatr Endocrinol，6(1)：21-31)。
通过使N-末端的D-Ala变成具有与在D-Phe和Lys之间插入的另一种氨基酸相连接的侧链的氨基酸，由称为GHRP-2的肽产生新的环状肽。此类肽中的一种(D-Lys-D-β-Nal-Ala-Trp-D-Phe-Glu-Lys-NH2)产生10倍于GHRP-6的体外活性和相当的体内功效(McDowe11 R.S.，等人(1995)Growth hormone secretagogues：characterization，efficacy，and minimal bioactive conformation.PNAS USA，92(24)：11165-11169)。完成了关于在DL环状肽溶液中的结构研究的实验，得出这样的结论，即在肽化合物中引入D氨基酸本质上是引发所需活性所需要的。其他研究旨在发现具有增加的口服生物利用率和更长的清除时间的活性分子，发现了新的GHRP和其他非肽性分子。在1993年，描述了第一种非肽性GH促分泌素(GHS)(SmithR.G.等人(1993)A nonpeptidy lgrowth hormone secretagogue.Science，260：1640-43)，并且随后涉及非肽性的且更有效的GHS——MK-0677的合成，其具有高生物利用率并且在单剂量口服施用后能够刺激GH分泌24小时(Patchett A.A.，NargundR.P.，等人(1995)Design andbiological activities of L-163，191(MK-0677)：a potent，orallyactive growth hormone secretagogue.PNAS USA，92：7001-7005；Smith R.G.，Van der Ploeg L.H.，等人(1997)Peptidomimeticregulation of growth hormone secretion.Endocr.Rev，18：621-645)。最近，设计了具有选择性的且有效的GH释放活性的另一 种拟肽GHS(EP1572)，其在人和动物组织中显示出类似于生长素释放肽(ghrelin)的GH促分泌素受体(GHS-R)结合效力，并且在皮下施用给新生大鼠后诱导GH的显著增加(Broglio F.，Boutignon F.等人(2002)EP1572：a novel peptido-mimetic GH secretagogue withpotent and selective GH-releasing activity in man.J EndocrinolInvest，25：RC26-RC28)。
在1999年，发现了生长素释放肽，其为主要在胃中产生的28个氨基酸的肽，然而，还在数种其他组织中发现了它的mRNA。它在胃中由X/A细胞产生，所述X/A细胞是泌酸粘膜中的主要内分泌细胞群。还在下丘脑弓状核中发现生长素释放肽，其中它的RNA存在于参与食欲控制和能量平衡的NPY和AGRP神经元中(Kojima M.，Hosoda H.等人(1999)Ghrelin is a growth-hormone-releasing acylatedpeptide from stomach.Nature，402：656-60；Nakazato M.，MurakamiN.等人(2001)A role for ghrelin in the central regulation offeeding.Nature，409：194-198)。它的RNA也定位于胰腺和肠中。它在成人的血流中以100-120fmol/ml的浓度循环，这暗示它由胃细胞分泌并且可能通过内分泌途径发挥作用。还报道了在赘生性组织中生长素释放肽的产生(Takaya K.，AriyasuH.等人(2000)Ghrelinstrongly stimulates growth hormone release in humans.J.Clin.Endocrinol.Metab，85：4908-11；PapottiM.等人(2001)Substantialproduction of ghrelin by a human medullary thyroid carcinomacell line.J Clin Endoc.Metab，86：4984-4990)。
其他动物研究显示，生长素释放肽的分泌是脉冲式的，并且相比于与GH脉冲而言与食欲更相关(Tolle V.，Bassant M.H.等人(2002)Ultradian rhythmicity of ghrelin secretion in relation with GH，feeding behaviour，and sleep wake patterns in rats.Endocrinology，143：1353-1361)。
生长素释放肽是第一种被发现其中丝氨酸之一的羟基被辛酸酰化的天然激素。据信这种修饰是与GHS-R1a的结合以及GH释放能力并且 可能是其他内分泌作用所必需的。
未酰化的生长素释放肽以比酰化的生长素释放肽更大的量循环，尽管对其未描述直接的内分泌作用，但据信其可能通过与其他亚型的GHS-R结合介导而发挥一些非内分泌功能，例如一般地心血管效应、心脏保护效应、抗增殖效应和细胞保护效应(Matsumoto M.，Hosoda H.等人(2001)Structure-activity relationship of ghrelin：pharmacological study of ghrelin peptides.Biochem Biophys ResCommun，287：142-146；Hosoda H.，Kojima M.等人(2000)Ghrelinand des-acyl ghrelin：two major forms of rat ghrelin peptidein gastrointestinal tissue.Biochem Biophys Res Commun，279：909-913；CassoniP.，Papotti M.等人(2001)Identification，characterization，and biological activity of specific receptorsfor natural(ghrelin)and synthetic growth hormone secretagoguesand analogs in human breast carcinomas and cell lines.J ClinEndocrinol Metab，86：1738-1745)。
可以从胃内分泌粘膜中分离出的GHS-Rla的另一种内源性配体是des-Glnl4-生长素释放肽，其是丢失了Gln14的生长素释放肽基因的备选加工的产物，并且与生长素释放肽一样，它在Ser3上经历了相同的酰化过程。
用具有由数种脂肪族或芳香族基团修饰的第3个残基的几种生长素释放肽类似物以及衍生自生长素释放肽的几种短肽所进行的研究显示，在残基3中的疏水基团是活性所必需的。还观察到包含生长素释放肽的前5个残基的短区段能够以与完整肽相当的功效激活受体。四肽显示出效力较低，并且缺乏N-末端的片段不能激活受体(BednarekM.A.，Feighner S.D.等人(2000)Structure-Function Studiesonthe New Growth Hormone-Releasing Peptide，Ghrelin：MinimalSequence of Ghrelin Necessary for Activation of Growth HormoneSecretagogue Receptor 1a.J Med Chem，43：4370-4376；Silva ElipeM.v.，Bednarek M.A.等人(2001)1H NMR structural analysis of human ghrelin and its six truncated analogs.Biopolymers，59：489-501)。此类研究暗示，完整的生长素释放肽序列不是活性所必需的，和Gly-Ser-Ser(n-辛酰基)-Phe是在作为GHS-R1a的激动剂的活性方面方面具有活性的片段。
在发现生长素释放肽之前和之后付出了极大努力，以发现可以作为GHS-R的配体的小分子和衍生物，大量专利描述了这种类型的分子(美国专利：US3,239,345；4,036,979；4,411,890；5,492,916；5,494,919；5,559,128；5,663,171；5,721,250；5,721,251；5,723,616；5,726,319；5,767,124；5,798,337；5,830,433；5,919,777；6,034,216；6,548,501；6,559,150；6,576,686；6,686,359；国际专利：wO89/07110；89/07111；92/07578；93/04081；94/11012；94/13696；94/19367；95/11029；95/13069；95/14666；95/17422；95/17423；95/34311；96/02530；96/15148；96/22996；96/22997；96/24580；96/24587；96/32943；96/33189；96/35713；96/38471；97/00894；97/06803；97/07117；97/09060；97/11697；97/15191；97/15573；97/21730；97/22004；97/22367；97/22620；97/23508；97/24369；97/34604；97/36873；97/38709；97/40023；97/40071；97/41878；97/41879；97/43278；97/44042；97/46252；98/03473；98/10653；98/18815；98/22124；98/46569；98/51687；98/58947；98/58948；98/58949；98/58950；99/08697；99/09991；99/36431；99/39730；99/45029；99/58501；99/64456；99/65486，99/65488；00/01726；00/10975；01/47558；01/92292；01/96300；01/97831)(Carpino，P.(2002)Recent developmentsin ghrelin receptor(GHS-.R1a)agonists and antagonists Exp.Opin.Ther.Patents12：1599-1618)。此类广泛修正后，描述了作为GHS-R的拮抗剂的其他化合物(US2005288316和wO2005048916)，并且描述了也与GHS-R结合并以各种目的进行使用的其他化合物(WO2005046682；WO2005039625；JP2003335752；US2004009984；US2003130284；wO03004518)。近来，在该集合中加入了个新系列的 大环化合物，主要目的是成为GHS-R的激动剂而不引起GH的释放(US2006025566)。
GHS-R是A类G偶联蛋白受体，其在人中由染色体3q26.2基因座中的单个基因表达。鉴定了由于前mRNA的备选加工而产生的两类cDNA(McKeeK.K.，TanC.P.等人(1997)Cloning and characterizationof two human G protein-cpupled receptor genes(GPR38and GPR39)related to the growth hormone secretagogue and neurotensinreceptors.Genomics，46：426-434；McKee K.K.，Palyha O.C.等人(1997)Molecular analysis of rat pituitary and hypothalamicgrowth hormone secretagogue receptors.Mol Endocrinol，11：415-423；US6,242,199；WO97/21730)。cDNA1a编码具有7个跨膜区段的366个氨基酸的受体(GHS-Rla)。cDNA1b编码具有289个氨基酸和5个跨膜区段的更短的蛋白质(GHS-Rlb)。尽管GHS-Rlb的作用仍是未知的，但已证实了其在数种内分泌和非内分泌组织中的表达(Howard A.D.，Feighner S.D.等人(1996)A receptor inpituitary and hypothalamus that functions in gr owth hormonerelease.Science，273：974-977；Gnanapavan S.，Kola B.等人(2002)The tissue distribution of the mRNA of ghrelin and subtypes ofits receptor，GHS-R，in humans.J Clin Endocrinol Metab.87：2988；Smith R.G.，Leonard R.等人(2001)Growth hormonesecretagogue receptor family members and ligands.Endocrine，14：9-14)。
人GHS-Rla与大鼠和猪的GHS-Rla分别具有96％和93％的同一性，并且在人GHS-Rla的序列与硬骨鱼的GHS-Rla序列显示出紧密关联。此类发现暗示，GHS-Rla在物种之间是高度保守的并且可能发挥基本的生物学功能(Palyha O.C.，FeighnerS.D.等人(2000)Ligandactivation domain of human orphan growth hormone(GH)secretagogue receptor(GHS-R)conserved from pufferfish tohumans.Mol Endocrinol.14：160-169)。
生长素释放肽和合成的GHS与GHS-Rla的结合激活磷脂酶C信号传导途径，增加肌醇-1，4，5三磷酸(IP3)的浓度和激活蛋白激酶C(PKC)，随后Ca2+从细胞内储库中释放。GHS-R的激活还抑制K+通道，使得能够通过L型电压门控通道而不是通过T型通道摄入Ca2+。与GHS-Rla不同，GHS-R1b不结合GHS或对GHS作出应答，并且它的功能仍是未知的(Chen C.，Wu D.等人(1996)Signal transduction systemsemployed by synthetic GH-releasing peptides in somatotrophs.J Endocrinol.148：381-386；Casanueva F.F.，Dieguez C.(1999)Neuroendocrine regulation and actions of leptin.FrontNeuroendocrinol，20：317-363；Howard A.D.，Feighner S.D.等人(1996)A receptor in pituitary and hypothalamus that functionsin growth hormone release.Science，273：974-977)。
合成的GHS、生长素释放肽及其天然同种型(des-Gln14-生长素释放肽)以高亲和力与GHS-Rla结合，并且置换膜结合的[35S]MK-0677或[125I][Tyr4]生长素释放肽的效率与刺激GH释放所需的浓度相关(Muccioli G.，Papotti M.等人(2001)Binding of125I-labeledghrelin to membranes from human hypothalamus and pi tuitarygland.J Endocrinol Invest.24：RC7-RC9；Hosoda H.，Kojima M.等人(2000)Purification and characterization of ratdes-Gln14-ghrelin，a second endogenous ligand for the growthhormone secretagogue receptor.J Biol Chem，275：21995-22000)。
为了测定生长素释放肽用于结合和激活GHS-Rla的基本结构特征，在表达人GHS-Rla的HEK-293细胞中研究了短的生长素释放肽，观察到包含生长素释放肽N-末端的具有4和5个氨基酸的肽能够激活该受体。基于该体外结构，假定Gly-Ser-Ser(n-辛酰基)-Phe基本上是激活该受体所必需的(Van der Lely A.J.，Tschop M.等人(2004)Biological，Physiological，Pathophysiological，andPharmacological Aspects of Ghrelin.Endocrine Reviews，25(3)：426-457)。生长素释放肽的前7个氨基酸在所有研究过的物种中是保 守的，然而，生长素释放肽衍生物在经转染的细胞中激活GHS-Rla的能力似乎不是在促生长激素细胞中刺激GH释放的能力的指示，近来显示，(1-4)和(1-8)辛酰基生长素释放肽无法在大鼠中刺激GH的释放，并且不能在人垂体或下丘脑膜制剂中有效地从结合位点上置换[125I][Tyr4]生长素释放肽(Torsello A.，Ghe C.等人(2002)Shortghrelin peptides neither displace ghrelin binding in vitro norstimulate GH release in vivo.Endocrinology，143：1968-1971)。在表达人或猪GHS-Rla的相同细胞中的其他研究发现，腺苷也激活该受体，但如短的生长素释放肽类似物一样无法刺激GH分泌，这暗示腺苷是GHS-Rla的部分激动剂并且和在受体中与MK-0677或GHRP-6不同的位点结合(SmithR.G.，Griffin P.R.等人(2000)Adenosine：apartial agonist of the growth hormone secretagogue receptor.Biochem Biophys Res Commun，276：1306-1313)。
近来已报告，GHS-Rla还可以结合皮质抑素(cortistatin)(CST)，所述皮质抑素是本身不能识别GHS-Rla的促生长素抑制素(SS)同系物神经肽(DeghenghiR.，PapottiM.等人(2001)Cortistatin，but not somatostatin，binds to growth hormone secretagogue(GHS)receptors of human pituitary gland.J Endocrinol Invest，24：RC1-RC3)。
GHS-Rla表达于弓状核和垂体促生长激素细胞(其是生长素释放肽和合成的GHS的神经内分泌和食欲刺激活性的关键区带)中(Willesen M.G.，Kristensen P.，Romer J.(1999)Co-localizationof growth hormone secretagogue receptor and NPY mRNA in thearcuate nucleus of the rat.Neuroendocrinology，70：306-316；Bluet-Pajot M.T.，Tolle V.等人(2001)Growth hormonesecretagogues and hypothalamic networks.Endocrine，14：1-8；Shintani M.，Ogawa Y.等人(2001)Ghrelin，an endogenous growthhormone secretagogue，is a novelorexigenic peptide thatantagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.Diabetes，50：227-232)。生长素释放肽和合成的GHS刺激神经元活性标记物(c-fos和EGR-1)在弓状核的神经元中的表达，并且在下丘脑外区域如海马外形的齿状扭转(dented twist)、海马的CA2和CA3区域、黑质致密部、腹侧被盖区、背侧和内侧中缝核、埃-韦核、桥和延髓(spinal bulb)中检测到GHS-R1a mRNA，这暗示可能的下丘脑外作用。也已在几个外周器官上发现其mRNA，如胃、肠、胰腺、肾、心脏、主动脉、几种人腺瘤以及某些人肺、胃和胰腺赘生物(Hewson A.K.，Dickson S.L.(2000)Systemic administration of ghrelin inducesFos and Egr-1proteins in the hypothalamic arcuate nucleus offasted and fedrats.J Neuroendocrinol，12：1047-1049；MuccioliG.，Ghe等人(1998)Specific receptors for synthetic GHsecretagogues in the human brain and pituitary gland.JEndocrinol，157：99-106；Guan X.M.，YuH.等人(1997)Distributionof mRNA encoding the growth hormone secretagogue receptor inbrain and peripheral tissues.Brain Res Mol Brain Res，48：23-29；Mori K.，Yoshimoto等人(2000)Kidney produces a novelacylated peptide，ghrelin.FEBS Lett，486：213-216；Nagaya N.，Miyatake K.等人(2001)Hemodynamic，renal，and hormonal effectsof ghrelin infusion in patients with chronic heart failure.JClin Endocrinol Metab，86：5854-5859；Korbonits M.，Bustin S.A.等人(2001)The expression of the growth hormone secretagoguereceptor ligand ghrelin in normal and abnormal human pituitaryand other neuroendocrine tumours.J Clin Endocrinol Metab，86：881-887；Papotti M.，Cassoni P.等人(2001)Ghrelin-producingendocrine tumors of the stomach and intestine.J Clin EndocrinolMetab，86：5052-5059)。
生长素释放肽和GHS对GHS-R1a具有高亲和力。然而，存在其他另外的关于GHS的位点的证据。已在人和大鼠心脏以及许多其他非内 分泌外周组织(如肺、动脉、骨骼肌、肾和肝)中发现关于Tyr-Ala-海沙瑞林(hexarelin)和其他GHS的特异位点，其具有至少等于在垂体中发现的密度的相似的受体密度(MuccioliG.，Ghe C.等人(1998)Specific receptors for synthetic GH secretagogues in the humanbrain and pituitary gland.J Endocrinol，157：99-106；MuccioliG.，Broglio .等人(2000)Growth hormone-releasing peptides andthe cardiovascular system.Ann Endocrinol(Paris)，61：27-31；Bodart V.，Bouchard J.F.等人(1999)Identification andcharacterization of a new growth hormone-releasing peptidereceptor in the heart.Circ Res，85：796-802；Katugampola S.，Davenport A.(2003)Emerging roles for orphan G protein-coupledreceptors in the cardiovascular system.Trends Pharmacol Sci，24：30-35；Ghigo E.，Arvat E.等人(2001)Biologic activitiesof growth hormone secretagogues in humans.Endocrine，14：87-93；Papotti M.，Ghe C.，Cassoni P.等人(2000)Growth hormonesecretagogue binding sites in peripheral human tissues.J ClinEndocrinol Metab，85：3803-3807)。此类结合位点显示出对于生长素释放肽的低亲和力，并且可能不是生长素释放肽受体而是生长素释放肽的肽性类似物受体。
心脏GHS-R具有比GHS-Rla更高的分子量(84kDa)并且无序列同源性，心脏中的该受体的预测氨基酸序列相似于CD36(PapottiM.，GheC.等人(2000)Growth hormone secretagogue binding sites inperipheral human tissues.J Clin Endocrinol Metab，85：3803-3807；Bodart V.，Febbraio M.等人(2002)CD36mediates thecardiovascul araction of growth hormone-releasing peptides inthe heart.Circ Res，90：844-849)。外周组织GHS受体的功能意义和在心血管系统中的发现暗示，此类结合位点调节肽性GHS的心脏保护活性。
生长素释放肽和合成的促分泌素在体外可能通过膜去极化和通过 每个细胞分泌的GH的增加来刺激促生长激素细胞对GH的释放，并且还报告了GHS对GH合成的刺激效应(Kojima M.，Hosoda H.等人(1999)Ghrelin is a growth-hormone-releasing acylated peptide fromstomach.Nature，402：656-660；Sartor O.，Bowers C.Y.，ChangD.(1985)Parallel studies of His-DTrp-Ala-Trp-DPhe-Lys-NH2 andhuman pancreatic growth hormone releasing factor-44-NH2 in ratprimary pituitary cell monolayer culture.Endocrinology，116：952-957；Bowers C.Y.，Sartor A.O.等人(1991)On the actions ofthe growth hormone-releasing hexapeptide，GHRP.Endocrinology，128：2027-2035；Wu D.，Chen C.等人(1994)The effect ofGH-releasing peptide-2(GHRP-2or KP102)on GHsecretion fromprimary cultured ovine pituitary cells can be abolished by aspecific GH-releasing factor(GRF)receptor antagonist.JEndocrinol，140：R9-R13)。
早期研究显示，GHS使用与GHRH不同的受体和途径刺激GH分泌：GHRH受体的拮抗剂抑制由GHRH引起的GH分泌，而不抑制由促分泌素刺激引起的GHRH的释放，并且假设的GHS-R拮抗剂不影响响应于GHRH的GH释放，GHRP-6在受体结合测定法中不与GHRH竞争GHRH结合位点，在GHS和GHRH共施用后存在对GH释放的累加效应，并且在GHRH和GHS之间就GH释放而言没有交叉脱敏(wu D.，Chen C.等人(1994)The effect of GH-releasing peptide-2(GHRP-2orKP102)on GHsecretion from primary cultured ovine pituitary cells can beabolished by a specific GH-releasing factor(GRF)receptorantagonist.J Endocrinol，140：R9-13；Thorner M.O.，Hartman M.L.等人(1994)Current status of therapy with growthhormone-releasing neuropeptides.Savage MO，Bourguignon J，Grossman AB(eds).Frontiers in Paediatric Neuroendocrinology，161-167)。
GHS的GH释放活性在垂体-下丘脑制剂中比在分离的垂体中更大， 这与更大的体内GH刺激效应的证据相一致(Mazza E.，Ghigo E.等人(1989)Effect of the potentiation of cholinergic activity onthe variability in individual GHresponse to GH-releasinghormone.J Endocrinol Inyest，12：795-798；Bowers C.Y.，SartorA.O.等人(1991)On the actions of the growth hormone-releasinghexapeptide，GHRP.Endocrinology，128：2027-2035；Clark R.G.，Carlsson M.S.等人(1989)The effects of a growthhormone-releasing peptide and growth hormone releasing factorin conscious and anaesthetized rats.J Neuroendocrinol，1：249-255)。
在下丘脑水平上，生长素释放肽和GHS作用于分泌GHRH的神经元，并且在对绵羊施用GHS后在垂体门脉循环中观察到增加的GHRH水平(Conley L.K.，Teik J.A.等人(1995)Mechanism of action ofhexarelin and GHRP-6：analysis of the involvement of GHRH andsomatostatin in the rat.Neuroendocrinology，61：44-50；Guillaume V.，Magnan E.等人(1994)Growth hormone(GH)-releasinghormone secreti on is stimulated by a new GH-releasinghexapeptide in sheep.Endocrinology，135：1073-1076)。
GHS需要GHRH以充分发挥其GH释放效应，在人中GH应答被GHRH受体拮抗剂和垂体-下丘脑切断所抑制(Bluet-Pajot M.T.，Tolle V.，等人(2001)Growth hormone secretagogues and hypothalamicnetworks.Endocrine，14：1-8；148：371-380；Popovic V.，MiljicD.，等人(2003)Ghrelin main action on the regulation of growthhormone release is exerted at hypothalamic level.J ClinEndocrinol Metab，88：3450-3453)。GHRH受体缺陷的患者不显示出作为对于GHS刺激的响应的GH分泌的增加，但保留在GHS刺激后增加皮质醇、ACTH和PRL的能力(Maheshwari H.G.，Pezzoli S.S.等人(2002)Pulsatile growth hormone secretion persists in geneticgrowth hormone-releasing hormone resis tance.Am J Physiol EndocrinolMetab，282：E943-E951；Maheshwari H.G.，Rahim A.等人(1999)Selective lack of growth hormone(GH)response tothe GH-releasing peptide hexarelin in patient swithGH-releasing hormone receptor deficiency.J Clin EndocrinolMetab，84：956-959；Gondo R.G.，Aguiar-O liveira M.H.，HayashidaC.Y.等人(2001)Growth hormone-releasing peptide-2 stimulatesGHsecretion in GH-deficient patients with mutated GH-releasinghormone receptor.J Clin Endocrinol Metab，86：3279-3283)。
在动物和人中，有证据表明GHS和GHRH诱导同源而不是异源脱敏的证据。对于GHS活性的同源脱敏出现在GHS输注期间，但未出现在超过15天的间歇性每日口服或鼻施用该肽时(Ghigo E.，Arvat E.等人(1994)Growth hormone-releasing activity of hexarelin，a new synthetic hexapeptide，after intravenous，subcutaneous，intranasal，and oral administration in man.J Clin EndocrinolMetab，78：693-698；Ghigo E.，Arvat E.等人(1996)Short-termadministration of intranasal or oral hexarelin，a synthetichexapeptide，does not desensitize the growth hormoneresponsiveness in human aging.Eur J Endocrinol，135：407-412)。另一方面，GHS的肠胃外、鼻内或口服施用在年轻的健康成人中增加GH自发性脉冲并升高IGF-1水平，如在儿童和老年受试者中(ChapmanI.M.，Bach M.A.等人(1996)Stimulation of the growth hormone(GH)-insulin-like growth factor I axis by daily oraladministration of a GHsecretagogue(MK-677)in healthy elderlysubjects.J Clin Endocrinol Metab，81：4249-4257；Copinschi G.，Van Onderbergen A.等人(1996)Effects of a 7-day treatment witha novel，orally active，growth hormone(GH)secretagogue，MK-0677，on24-hour GH profiles，insulin-like growth factor I，andadrenocortical function in normal young men.J Clin EndocrinolMetab，81：2776-2782；Laron Z.，Frenkel J.等人(1995)Intranasal administration of the GHRP hexarelin accelerates growth inshort children.Clin Endocrinol(Oxf)，43：631-635)。
生长素释放肽在大鼠中能够刺激食欲，并且这种性质可以通过NPY和AGRP的合成来介导。心室内的生长素释放肽还能够取消瘦蛋白的减食欲效应，并且推断在这2种肽之间存在对食欲和能量稳态控制的竞争性相互作用。大鼠中生长素释放肽的循环浓度在禁食时增加，并且在摄食或葡萄糖摄入后变小(Shintani M.，Ogawa Y.等人(2001)Ghrelin，an endogenous growth hormone secretagogue，is a novelorexigenic peptide that antagonizes leptin action through theactivation of hypothalamic neuropeptide Y/Y1 receptor pathway.Diabetes，50：227-32；Nakazato M.，Murakami N.等人(2001)A rolefor ghrelin in the central regulation of feeding.Nature，409(6817)：194-198；Tsch
p M.，Smiley D.L.，Heiman M.L.(2000)Ghrelin induces adiposity in rodents.Nature，407：908-13)。
GHS还刺激食欲和重量增长。在NPY缺陷型小鼠中使用GHRP-2的长期处理刺激脂肪组织的积累，并且增加对照中AGRP mRNA的下丘脑表达(Torsello，A.，Luoni，M.等人(1998)Novel hexarelin analogsstimulate feeding in the rat through a mechanism not involvinggrowth hormone release.Eur.J.Pharmacol，360：123-129；Ghigo，E.，Arvat，E.等人(1999)Endocrine and non-endocrine activitiesof growth hormone secreta gogues in humans.Horm.Res，51：9-15；Tschop，M.，Statnick等人(2002)GH-releasing peptide-2 increasesfat mass in mice lacking NPY：indication for a crucial mediatingrole of hypothalamic agouti-related protein.Endocrinology，143：558-568)。
对大鼠施用生长素释放肽通过脂肪组织的显著增加来产生食欲和重量的增加，而未观察到瘠瘦质量、骨组织或生长刺激的变化。生长素释放肽的脂肪生成效应不依赖于GH作用，并且它可以在GH遗传缺陷的大鼠中被发现。GH引起能量消耗的增加并导致脂肪消除，这允许 与生长素释放肽的平衡：生长素释放肽增加脂肪组织，而GH不允许瘠瘦组织的减少(Nakazato M.，Murakami N.等人(2001)A role forghrelin in the central regulation of feeding.Nature，409(6817)：194-198；Wren A.M.，Small C.J.等人(2000)The novel hypothalamicpeptide ghrelin stimulates food intake and growth hormonesecretion.Endocrinology，141(11)：4325-4328；Tschop M.，Smiley D.L.，Heiman M.L.(2000)Ghrelin induces adiposity inrodents.Nature，407：980-913)。
在肥胖个体中，生长素释放肽水平被耗竭，并且在摄食后不减少，这是可逆的状况，因为重量减轻和生长素释放肽平均血浆水平是增加的。生长素释放肽的血浆水平与体重指数、体脂重量、肥胖的大小以及胰岛素、葡萄糖和瘦蛋白的血浆水平负相关(English P.J.，GhateiM.A.等人(2002)Food fails to suppress ghrelinl evels in obesehumans.J Clin Endocrinol Metab，87(6)：2984；Tschop M.，Weyer C.等人(2001)Circulating ghrelin levels are decreasedin human obesity.Diabetes，50(4)：707-9)。
已报告，肥胖患者中GH不足在延长的饮食和显著的重量减轻后是可逆的。游离脂肪酸的长期增加和与低生长素释放肽水平相关的胰岛素分泌过多可能在引起肥胖症中的GH不足方面具有重要作用(Maccario M.，Tassone F.，Grotto1i S.，Rossetto R.，Gauna C.，Ghigo E.(2002)Neuroendocrine and metabolic determinants ofthe adaptation of GH/IGF-I axis to obesity.Ann Endocrinol(Paris)，63(2Pt1)：140-144)。
因为发现生长素释放肽是脂肪生成性的和促进食欲的，所以可以认为通过拮抗它来进行肥胖症治疗，然而，此类拮抗的结果减少GH分泌并且与脂肪量增加相关(Jorgensen J.O.，Vahl N.，(1996)Inf luence of growth hormone and androgens on body compositionin adults.Horm Res，45：94-98)。生长素释放肽的激动剂或拮抗剂的长期施用将揭示2种效应中的哪一种占优势并确定其对能量平衡 的影响。
在肥胖男性中，生长素释放肽的循环浓度减少，并且与体脂组织以及胰岛素和瘦蛋白的循环水平负相关(Tsch
p M.，Weyer C.等人(2001)Circulating ghrelinl evels are decreased in humanobesity.Diabetes，50：707-9)。
GH/IGF-I轴在心脏发育期间以及对于心脏的结构或功能的维持具有非常重要的作用；关于心血管性能的恶化是可以用GH疗法恢复的GH缺乏的症状之一(SaccaL，Cittadini A，Fazio S(1994)Growthhormone and the heart.Endocr Rev15：555-573；Caidahl K，EdenS，Bengtsson B
1994 Cardiovascular and renal effects of growthhormone.Clin Endocrinol(Oxf)40：393-400)。
存在实验数据显示了由于GH而出现心肌性能方面的改善，其中许多研究使用在大鼠中的心肌梗塞(MI)模型，在MI后的GH处理导致收缩期射血体积、心输出量和其他收缩期变量方面的增加，连同由于GH/IGF-I的显著的血管舒张和较低的总外周阻力，这可能有助于改善心肌收缩性(Timsit J，Riou B等人1990Effects of chronic growthhormone hypersecretion on intrinsic contractility，energetics，isomyosin pattern and myosin adenosine triphosphate activityof rat left ventricle.J Clin Invest86：507-515；Tajima M，等人(1999)Treatment with growth hormone enhances contractilereserve and intracellular calcium transients in myocytes fromrats with post infarction heart failure.Circulation99：127-134)。
另一方面，具有过量的GH的动物模型显示出向具有低腺苷三磷酸酶活性的肌球蛋白同种型的转变，它们可能降低收缩过程中的能量需求(Timsit J，Riou B等人(1990)Effects of chronic growth hormonehypersecretion on intrinsic contractility，energetics，isomyosin pattern and myosin adenosine triphosphate activityof rat left ventricle.J Clin Invest86：507-515)。
存在几项针对GH和/或IGF-I的心脏和外周效应的研究，其中良好的临床数据指出GH/IGF-I在心血管治疗中的未来作用(Fazio S.，Sabatini D.等人(1996)A preliminary study of growth hormonein the treatment of dilated cardiomyopathy.N Eng1 J Med，334：809-814)。
数种合成的GHS和生长素释放肽在几项体内研究中具有心脏保护性质，其中它们改善了几种心脏功能变量，具有与GH相当的效应。海沙瑞林血液动力学特性曲线与GH的相似性可能暗示GHS作用由GH介导，然而，近期研究支持对心脏的直接作用(Locatelli V.，RossoniG.，(1999)Growth Hormone independent cardioprotective effectsof hexarelin in the rat.Endocrinology，140：4024-4031；Tivesten 
.，Bollano E.，(2000)The growth hormone secretagogue hexarelinimproves cardiac function in rats after experimental myocardialinfarction.Endocrinology，141：60-66)。
已在主动脉和心脏中发现GHS-R1a mRNA，并且在与海沙瑞林预温育后其在心肌细胞培养物中也是增加的(Gnanapavan S.，Kola B.等人(2002)The tissue distribution of the mRNA of ghrelin andsubtypes of its receptor，GHS-R，in humans.J Clin EndocrinolMetab，87：2988-2991；Nagoya N.，Kojima M.等人(2001)Hemodynamicand hormonal effects of human ghrelin in healthy volunteers.Am J Physiol Regul Integr Comp Physiol，280：R1483-R1487；PangJ.-J.，Xu R.-K.等人(2004)Hexarelin protects rat cardiomyocytesfrom angiotensin II-induced apoptosis in vitro.Am J PhysiolHeart Circ Physiol，286(3)：H1063-1069)。
已在大鼠心脏和人动脉中鉴定了特异性的生长素释放肽结合位点，其中受体密度随着动脉粥样硬化而增加，并且发现放射性标记的肽性GHS以比与垂体结合更高的量与大鼠心肌细胞和几种人心血管组织(心室、心房、主动脉、冠状动脉、颈动脉、心内膜和腔静脉)特异性结合(Katugampola S.D.(2001)[125I-His(9)]-ghrelin，a novel radioligand for localising GHS orphan receptors in humanand rat tissue：up-regulation of receptors with atherosclerosis.Br J Pharmacol，134：143-149；Ong H.，McNicoll N.等人(1998)Identification of a pituitary growth hormone-releasing peptide(GHRP)receptor subtype by photo affinity labeling.Endocrinology，139：432-435；Bodart V.，McNicoll N.等人(1999)Identification and characterization of a new GHRP receptor inthe heart.Circ Res，85：796-808；Papotti M.，Ghe C.等人(2000)Growth hormone secretagogue binding site in periferical humantissues.J Clin Endocrinol Metab，85：3803-3807)。
尽管高药理学剂量的肽性GHS的施用在预灌注的大鼠心脏中诱导明确但暂时的血管收缩，其中使用具有通过针对GHRH进行免疫接种而诱导的GH缺乏的年轻大鼠，但是还发现海沙瑞林可以保护不受由缺血和再灌注诱导的心肌损伤，此类保护活性与前列环素释放和血管紧张素II血管加压活性的恢复相关(Bodart V.，Febbario M.等人(2000)CD36 mediates the cardiovascular action of growthhormone-releasing peptides in the heart.CircRes，90：844-849；de Gennaro Colonna V.，Rossoni G.等人(1997)Hexarelin，a growthhormone-releasing peptide，discloses protectant activityagainst cardiovascular damage in rats with isolated growthhormone deficiency.Cardiologia，42：1165-1172；de GennaroColonna V.等人(1997)Cardiac ischemia and impairment ofvascular endothelium function in hearts from growthhormone-deficient rats：protection by hexarelin.EurJPharmacol，334：201-207)。
在老年大鼠中获得相似结果，其中用海沙瑞林进行的处理导致针对缺血后心室功能障碍的强力保护。在再灌注中观察到心脏功能的完全恢复，并且肌酸激酶水平的同时减少证实了在氧重新接纳后心肌膜的细胞的完整性和收缩无力的保留。通过6-酮-PGF1a的产生和对血管 紧张素II的冠状动脉血管反应性的恢复也显示了海沙瑞林的保护效应(Rossoni G.，de Gennaro Colonna V.等人(1998)Protectantactivity of hexarelin or growth hormone against post ischemicventricular dysfunction in hearts from aged rats.J CardiovascPharmacol，32：260-265；Rossoni G.，de Gennaro Colonna V.等人(1998)Protectant activity of hexarelin or growth hormoneagainst post ischemic ventricular dysfunction in hearts fromaged rats.J Cardiovasc Pharmacol，32：260-265；Locatelli V.，Rossoni G.等人(1999)Growth hormone-independentcardioprotective effects of hexarelin in the rat.Endocrinology，140：4024-4031)。在切除了垂体的大鼠中的研究显示了GHS心脏保护效应，其不依赖于GH并且由特异性心肌受体介导(Locatelli V.，Rossoni G.等人(1999)Growth hormone-independentcardioprotective effects of hexarelin in the rat.Endocrinology，140：4024-4031；Bodart V.，McNicoll N.等人(1999)Identification and characterization of a new GHRP receptor inthe heart.Circ Res，85：796-808)。
海沙瑞林在心肌梗塞诱导后的4周龄大鼠模型中增加收缩期射血体积和心输出量，并减少总外周阻力。尽管合成的GHS的收缩能活性的机制不明，但有证据表明通过作用于内皮细胞或神经末梢而增加了乳头肌收缩性(Tivesten A.，Bollano等人(2000).The growth hormonesecretagogue Hexarelin improve cardiac function in ratsafterexperimental myocardial infarction.Endocrinology，141：60-66；Bedendi I.，Gallo M.P.等人(2001)Role of endothelial cells inmodulation of contractility induced by hexarelin in ratventricle.Life Sci，69：2189-2201)。
生长素释放肽不完全具有合成GHS的所有心血管作用，生长素释放肽对心脏具有弱保护，这暗示合成GHS的效应是由于GHS特异性位点的结合和激活。用[125I]Tyr-Ala-海沙瑞林的研究揭示了在大鼠心 肌和人心血管组织中不同于GHSR-1a的许多结合位点，这暗示了另一种受体的存在，其具有与介导合成GHS的冠状动脉作用的CD36类似的序列(Torsello A.，Bresciani E.等人(2003)Ghrelin plays a minorrole in the physiological control of cardiac function in therat.Endocrinology，144：1787-1792；Muccioli G.，Broglio F.等人(2000)Growth hormone-releasing peptides and thecardiovascular system.Ann Endocrinol(Paris)61：27-31；BodartV.，Febbraio M.等人(2002)CD36mediates the cardiovascularaction of growth hormone-releasing peptides in the heart.CircRes，90：844-849)。尽管生长素释放肽在冠状动脉水平上大部分是无活性的，但它呈现出其他心血管效应，生长素释放肽具有非常有效的体内和体外血管舒张效应，此类生长素释放肽作用针对非横纹肌，并具有与利尿钠肽相当的效力。在人动脉粥样硬化患者中，生长素释放肽受体是增加的，这暗示它在对此类病状中观察到的血管收缩增加的补偿之中发挥作用(Okumura H.，Nagaya N.等人(2002)Vasodilatory effect of ghrelin，an endogenous peptide from thestomach.J Cardiovasc Pharmacol，39：779-783；Wiley K.E.，Davenport A.P.(2002)Comparison of vasodilators in humaninternal mammary artery：ghrelin is a potent physiologicalantagonist of endothelin-1.Br.J.Pharmacol，136：1146-1152；Katugampola S.D.(2001)[125I-His(9)]-ghrelin，a novelradioligand for localising GHS orphan receptors in human andrat tissue：up-regulation of receptors with atherosclerosis.Br J Pharmacol，134：143-149)。
其他研究显示，海沙瑞林、酰化的生长素释放肽和甚至生长素释放肽可以预防多柔比星诱导的H9c2心肌细胞和内皮细胞的细胞死亡，其可能是刺激了细胞内信号传导，如ERK1/2和PI3-激酶/AKT的激活(Baldanzi G.，Filigheddu N.等人(2002)Ghrelin and des-acylghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2andPI3-kinase/AKT.J Cell Biol，159：1029-1037；Filigheddu N.，Fubini A.等人(2001)Hexarelin protectsH9c2 cardiomyocytes from doxorubicin-induced cell death.Endocrine，14：113-119)。
对于心肌细胞和内皮细胞的体内研究暗示，GHS的抗凋亡效应通过激活ERK和AKT以及通过抑制胱天蛋白酶3的激活及BAX的表达和BCL-2表达的增加来介导(Pang J.J.，Xu R.K.等人(2004)Hexarelinprotects rat cardiomyocytes from angiotensin II-inducedapoptosis in vitro.Am J Physiol Heart Circ Physiol，286：H1063-H1069)。这些数据支持存在另一种GHS-R亚型的假设，因为非酰化的生长素释放肽不激活GHS-R1a。
生长素释放肽和GHS在人中具有真正的心血管活性，对健康志愿者和具有慢性心力衰竭的患者施用生长素释放肽和GHS减少了全身血管阻力，并增加心输出量和收缩期射血体积，伴随着平均动脉压的减少，但未显示心率、内侧肺动脉的压力或肺毛细血管压方面的任何变化(Nagaya N.，Kojima M.等人(2001)Hemodynamic and hormonaleffects of human ghrelin in healthy volunteers.Am J PhysiolRegul Integr Comp Physiol，280：R1483-R1487；Enomoto M.，NagayaN.等人(2003)Cardiovascular and hormonal effects ofsubcutaneous administration of ghrelin，a novel growthhormone-releasingpeptide，in healthy humans.Clin Sci(Lond)，105：431-435)。
还已观察到几种营养因子(包括GH和IGF-I)在体内低氧缺血(HI)的第二阶段期间中具有神经保护性质，并且已显示，随后引起AKT磷酸化的PI3K途径的激活调节在体外生长因子诱导的神经元存活率，磷酸化的AKT延长细胞存活并可以抑制由于几种抗凋亡靶(如Bad、糖原合酶3β(GSK3β)、胱天蛋白酶9)的失活或者转录因子的修饰而引起的凋亡(Kulik G.，Klippel A.，Weber M.J.(1997).Antiapoptotic signalling by the insulin-like growth factor I receptor，phosphatidylinositol 3-kinase，and Akt.Mol Cell Biol，17：1595-1606)。
由生长因子激活的另一种途径是MAPKp42/44ERK。发现ERK激活抑制低氧诱导的凋亡。此外，已显示新生大鼠中由BDNF引起的神经保护经由MAPK/ERK的激活介导，并且HI后的IGF-I处理激活Akt和EKR(Buckley S.，Driscoll B.等人(1999)ERK activation protectsagainst DNA damage and apoptosis in hyperoxic rat AEC2.Am JPhysiol，277：159-166；Han B.H.，Holtzman D.M.(2000)BDNF protectsthe neonatal brain from hypoxic-ischemic injury in vivo via theERK pathway.J Neurosci，20：5775-5781)。
海沙瑞林在HI的体内模型中减少脑损害。这种保护涉及AKT和GSK3β磷酸化，这表明涉及PI3K途径的可能性，其中在皮质、海马、丘脑中观察到保护效应但在纹状体中未观察到保护效应，保护的空间分布与GH受体和海沙瑞林的定位相关(Brywe K.G.，Leverin A.-L.等人(2005)Growth Hormone Releasing Peptide Hexarelin reducesneonata lbrain injury and alters Akt/Glycogen SynthaseKinase-3
phosphorylation.Endocrinology，146：4665-4672；LobieP.E.，Garcia-AragónJ.等人(1993)Localization and ontogeny ofgrowth hormone receptor gene expression in the cent ral nervoussystem.Dev Brain Res，74：225-233；Scheepens A.，Sirimanne E.S.等人(2001)Growth hormone as a neuronal rescue factor duringrecovery from CNS injury.Neuroscience，104：677-687)。这些发现暗示，海沙瑞林保护效应可以是经GH介导的，或者GH和海沙瑞林共享用于细胞保护的共同途径，因为已在几种脑结构中发现了GHS-RmRNA。在生理条件下对成年大鼠施用GHRP-6显示出在下丘脑、小脑、海马中IGF-I水平的增加但在皮质中不增加。虽然这可能是由于IGF-I表达的增加，但在HI后24小时在用海沙瑞林处理的大鼠中未发现相同的效应。另一方面，如果IGF-I是海沙瑞林效应的介体，那么还可以预期纹状体中脑损害的减少，因为IGF-I受体存在于那里 (Frago L.M.，Paneda C.，Dickson S.L.等人(2002)Growth hormone(GH)and GH-releasingpe ptide-6 increase brain insulin-likegrowt hfactor-I expression and activate intracellularsignalling pathways involved in neuroprotection.Endocrinology，143：4113-4122；Guan J.，Williams C.等人(1993)The effects of IGF-1 treatment after hypoxic-ischemic braininjury in adult rats.J Cereb Blood Flow Metab，13：609-616)。海沙瑞林在HI后还激活中枢神经系统(CNS)中的PI3K途径，但它不影响ERK磷酸化，相反地，IGF-I激活ERK和PI3K途径。
海沙瑞林在不存在IGF-I的明显诱导的情况下增加IGF-I受体的磷酸化，这种磷酸化增加可以是由于经由海沙瑞林或内源性配体的受体反式激活。先前已报道，GPCR激动剂如血管紧张素II、凝血酶和内皮缩血管肽可以刺激IGF-I和/或AKT(Sumitomo M.，Milowsky M.I.等人(2001)Neutral endopeptidase inhibits neuropeptide-mediated transactivation of the insulin-like growth factorreceptor-Akt call survival pathway.Cancer Res，61：3294-3298；Zahradka P.，Litchie B.等人(2004)Transactivation of theinsulin-like growth factor-I receptor by angiotensin IImediates downstream signalling from the angiotensin II type 1receptor to phosphatidylinositol 3-kinase.Endocrinology，145：2978-2987)。
海沙瑞林的神经保护效应似乎并非主要通过GH/IGF-I轴的诱导来介导，尽管经过IGF-I受体的信号传导的增加可以促进脑损害的减少。
发明详述
尽管在现有技术中描述了关于这个领域的大量工作，然而，显而易见的是，所有生长素释放肽模拟化合物和非肽性质的化合物均不能 在生物体中发挥生长素释放肽所具有的所有可能功能，优选使用具有更大结构相似性的肽性质的化合物，然而，此类肽性类似物的描述局限于使用非天然D立体化学氨基酸作为组成的一部分。
考虑到肽性促分泌素在先前描述的功能中的重要性以及此类化合物对于各种各样的生物、系统和细胞中内分泌和非内分泌功能的能力，本发明事实上首次描述了肽性质的化学分子，其具有内部环并且仅由关于手性碳而言具有L立体化学的氨基酸组成，它们由于其化学结构而能够发挥与生长素释放肽、脱酰基生长素释放肽和其他肽性GHS相似的功能，包括但不限于GH释放能力，心脏保护和一般而言心肌和网状内皮系统的功能改善，神经保护(不仅包括脑还包括所有神经系统细胞)，以及食欲的控制和调节(包括脂肪和能量代谢的调节)。
本发明中描述的肽化合物具有使其满足下述要求的结构：即结合生长素释放肽特异性受体，并同时结合对于能够执行其他上述功能的其他促分泌素的结合所描述的受体。
在一个具体实施方案中，本发明涉及具有下述结构的化学分子：
I.[Aa1...Aan]X1[Ab1...Abn]X2[Ac1...Acn]Adn
其中，Aa是选自[Cys、Gly、Ser、His、Ala、Leu、Met或Thr]的L-氨基酸，在组合方面于1-4个残基之间变化；Ab是选自[Pro、Ile、Ala、Phe、Trp、Lys、Asp、Asn、Glu、Gln、Gly、Leu、Met、Tyr或Thr]的L-氨基酸，在组合方面于1-4个残基之间变化；Ac是选自[Arg、Leu、Pro、Val、Thr、Glu、His、Gln、Asn、Asp、Trp、Tyr、Phe、Ser、Ala、Gly或Ile]的L-氨基酸，在组合方面于1-5个残基之间变化；和Ad是天然或非天然的L-氨基酸，在数目方面没有限制；X1和X2是天然或非天然的L-氨基酸，具有共价结合的侧链从而形成内部环，其中使用任何化学反应用于直接连接或使用结合性化合物作为桥。
下面显示了属于所述结构类别的化合物：
A221 GSKFDSPEHQ (SEQ.ID NO：1)
A222 HGSKFDLEFG (SEQ.ID NO：2)
A223 HCKFDLDWH (SEQ.ID NO：3)
A224 SSDFKLYWG (SEQ.ID NO：4)
A225 ALDFKPNIP (SEQ.ID NO：5)
A226 STDFKPFAI (SEQ.ID NO：6)
A227 HSKGYDLDH (SEQ.ID NO：7)
A228 GKFGDLSPEHQ (SEQ.ID NO：8)
A229 HAKPGGIDPEQ (SEQ.ID NO：9)
A230 GKFDSPEHQ (SEQ.ID NO：10)
A231 GGGKFWDIPHH (SEQ.ID NO：11)
A232 HKGIDSPEQH (SEQ.ID NO：12)
A233 GKFDLSPEHQ (SEQ.ID NO：13)
A234 GDAGAKLLSSR (SEQ.ID NO：14)
A235 GMEAGIKLCHRQ (SEQ.ID NO：15)
A236 GEGYKLDERSQ (SEQ.ID NO：16)
A237 GGEAGKLCPPRY (SEQ.ID NO：17)
A238 GLEFKLLHQ (SEQ.ID NO：18)
其中有下划线的氨基酸通过侧链连接。
通过人生长素释放肽受体的详尽分子建模来就所述功能对上述分子进行描述，其中使用同源性建模、分子动力学和详尽的构象搜索技术的组合技术。
一旦对受体进行了建模，就基于生长素释放肽和其他促分泌素的建模来构建结合模型，从受体-配体相互作用开始构建了具有数千种结构的虚拟文库，所述结构具有这样的特征以执行构象分析，并且针对该受体模型进行了大量对接实验。
基于这种分析，选择了代表数种结构家族的一系列化合物，其是化学合成的并用数种体内和体外系统进行了测试，在生物学测定法后，对所述化合物进行再优化并产生新文库，并且重复进行结构分析以寻找对生物系统的更大的作用，通过具有更特异的结构规律性。
本发明还包括上述化合物的任何同系物变体。“同系物变体”应 当理解为这样的任何分子，其化学性质在氨基酸序列方面70％或更高地类似于本发明中描述的化合物(前面的页)，包括非天然氨基酸，其具有允许其执行本文描述的化合物相同的效应的结构。
在本发明的另一个优选实施方案中，药物组合物包含一种或多种所描述的化合物或其可接受的盐，以及对于应用目的来说可接受的赋形剂或载体。本发明还包括所述化合物在制备用于人或兽医学使用的药剂、营养补充剂或者其他制剂中的用途，所述兽医学使用涉及水产养殖或者其他的动物饲养或改善活动，在体内、在体外、或者在与机体结合的装置或用于控制向介质中的释放的装置中，这与类似于其他GHS的作用相关联，与其内分泌作用直接相关或不相关。
通过与人生长素释放肽受体相互作用的能力来定义本文描述的分子，但不排除这样的其他蛋白质，其不具有相似的结构或氨基酸序列，但具有结合这类化合物的能力并以任何方式影响其生物学作用，通过激活、通过增强、通过抑制、通过与其他物质的竞争或协同、或者通过已描述或未描述但未通过实验证明的任何机制。
对于本发明中描述的化合物的定义，使用同源性建模、分子动力学和详尽的构象搜索技术的组合技术，对人生长素释放肽受体进行分子建模。一旦对受体进行了建模，就基于生长素释放肽和其他促分泌素的建模来构建结合模型，从受体-配体相互作用开始构建了具有数千种结构的虚拟文库，所述结构具有这样的特征以执行构象分析，并且针对该受体模型进行了大量对接实验。
基于这种分析，选择了代表数种结构家族的一系列化合物，其是化学合成的并用数种体内和体外系统进行了测试，在生物学测定法后，对所述化合物进行再优化并产生新文库，并且以用受体实施另一轮分子对接来重复进行结构分析从而提取出精确结构规律性，对第二轮的化学性质进行优化以达到在-58和-32KJ/mol之间的计算出的结合能的更高值，并再次进行分析以寻找对生物系统更大的作用，通过具有更特异的结构规律性。对具有优于-40KJ/mol的结合能的18种此类化合物的代表性选择进行合成，使用高效液相色谱法进行纯化，通过 质谱法进行分析，并就体内和体外功效进行评估。
附图简述
图1：使用化合物A221(a)、A228(b)和A233(c)进行处理在预防由多柔比星(Dx)诱导的心肌衰竭中的效应。
图2：化合物A221(a)、A228(b)和A233(c)在经Dx处理的大鼠中对于强迫应激(forced stress)的保护效应。
图3：在使用100-500μg/kg动物体重的剂量的处理组中，用化合物A221(a)、A228(b)和A233(c)进行处理在由多柔比星(Dx)诱导的扩张型心肌病的时间和逆转中的效应。
图4：用化合物A221(a)、A228(b)和A233(c)进行处理在具有由多柔比星(Dx)诱导的扩张型心肌病的动物的存活中的效应。
实施例
在下述实施例中说明本发明：
实施例1：通过计算机分子建模来选择化合物。
对在第二个循环的如上所述的计算评估中获得的化合物进行优化，以获得在受体结合时更佳的能量值和更特异的规律性，如表1中所示选择了具有优于-40KJ/mol的能量的18种代表性化合物。
表1.计算出的在分子对接后与生长激素促分泌素受体模型相互作用的能量。
| 化合物 | 能量(KJ/mol) | 化合物 | 能量(KJ/mol) |
| A221 | -52.54 | A230 | -56.27 |
| A222 | -49.80 | A231 | -42.32 |
| A223 | -43.76 | A232 | -50.30 |
| A224 | -42.93 | A233 | -58.06 |
| A225 | -54.99 | A234 | -53.14 |
| A226 | -40.00 | A235 | -45.94 |
| A227 | -41.01 | A236 | -45.20 |
| A228 | -40.93 | A237 | -50.01 |
| A229 | -52.25 | A238 | -51.11 |
实施例2：防止由NGF剥夺诱导的PC12细胞的死亡。
在75cm2培养瓶中，于50μg/ml庆大霉素存在下将PC12细胞贮存于包含5％胎牛血清和10％马血清的DMEM中。细胞于37℃在CO2中进行温育。为了诱导分化，将细胞以1×104的密度转移至经聚赖氨酸包被的96孔平板中的补充有NGF的DMEM培养基之中7天，每2-3天更换培养基。在分化后，将细胞与不同浓度的类似于肽性GHS的化合物一起温育72小时。
使用非放射性Cell Titer96增殖/细胞毒性测定法(Promega)来测定细胞存活和增殖，其基于溴化3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四唑鎓(MTT)转化成通过分光光度法可检测的产物。在NGF剥夺后，去除培养基并加入15μ1溶解在DMEM中的染料，在于37℃温育4小时后，加入100μl终止溶液，并在570nm处测量吸光度。
所述化合物显示出浓度依赖性神经保护效应。每种化合物的IC50显示于表2中。
表2.在由NGF剥夺诱导的神经元死亡期间每种化合物的IC50值。
| 化合物 | IC50uM | 化合物 | IC50uM |
| A221 | 2.02 | A230 | 4.06 |
| A222 | 2.03 | A231 | 4.00 |
| A223 | 3.12 | A232 | 4.89 |
| A224 | 2.37 | A233 | 5.00 |
| A225 | 4.07 | A234 | 5.86 |
| A226 | 4.87 | A235 | 2.05 |
| A227 | 3.06 | A236 | 3.00 |
| A228 | 3.99 | A237 | 3.33 |
| A229 | 3.41 | A238 | 2.04 |
实施例3：防止通过向神经元原代培养物中添加过氧化氢而诱导的神经元损害。
小脑颗粒细胞的原代培养物得自7-9天的Wistar大鼠。在快速解剖后，将大鼠小脑浸入冷溶液中，并去除脑膜，将每种器官转移至2-3ml新鲜的培养基溶液中并精细地切片。使用巴斯德吸管(Pasteurpipette)来分离细胞，并通过40mu.M尼龙膜(Falcon，FranklinLakes，N.J.)进行过滤。通过用台盼蓝作为标记在血细胞计数器中施行细胞计数来测定活细胞的数目。在经聚赖氨酸包被的96孔平板中以在200ml终体积中6250个细胞的密度培养细胞。培养物于37℃保持在5％CO2中，24小时后，加入10μM胞嘧啶阿拉伯呋喃糖(AraC；Sigma)以抑制非神经元细胞的增殖。
于24小时，在不同浓度的类似于肽性GHS的化合物下测试防止由加入500μM过氧化氢而诱导的神经元损害的能力，其中使用非放射性Cell Titer96增殖/细胞毒性测定法(Promega)来测定细胞存活。
所述化合物显示出浓度依赖性神经保护效应。每种化合物的IC50显示于表3中。
表3.在由向神经元原代培养物中添加过氧化氢而诱导的神经元损害的防止实验期间
每种化合物的IC50值。
| 化合物 | IC50uM | 化合物 | IC50uM |
| A221 | 1.80 | A230 | 3.81 |
| A222 | 1.30 | A231 | 3.46 |
| A223 | 2.47 | A232 | 3.28 |
| A224 | 3.20 | A233 | 3.56 |
| A225 | 3.99 | A234 | 3.72 |
| A226 | 3.58 | A235 | 1.01 |
| A227 | 2.26 | A236 | 3.33 |
| A228 | 1.77 | A237 | 2.51 |
| A229 | 1.33 | A238 | 1.00 |
实施例4：类似于肽性GHS的化合物在鱼类中的生物学活性的证实。
在经腹膜内注射的罗非鱼的肝脏中测定IGF-ImRNa，还监控GH水平的时间曲线，显示出类似肽性GHS的化合物能够在鱼类中刺激血流中的GH水平，并在注射化合物后增加IGF-ImRNA水平，如表4中所示。
表4.针对使用无关的合成肽的对照组进行标准化的IGF-ImRNA水平。
| 化合物 | IGF1 | 化合物 | IGF1 |
| A221 | 1.32 | A230 | 1.48 |
| A222 | 1.115 | A231 | 1.39 |
| A223 | 1.40 | A232 | 1.23 |
| A224 | 1.41 | A233 | 1.69 |
| A225 | 1.38 | A234 | 1.17 |
| A226 | 1.13 | A235 | 0.9 |
| A227 | 1.28 | A236 | 1.13 |
| A228 | 1.18 | A237 | 1.201 |
| A229 | 1.09 | A238 | 1.24 |
实施例5：在用类似于肽性GHS的化合物进行处理的幼年罗非鱼中进 行 的生长实验：
5.1在经腹膜内(ip)途径用类似于肽性GHS的化合物处理的罗非鱼中生长加速。
将化合物溶解于磷酸钠(PBS)缓冲溶液中，并在3周期间内以0.1μg/g鱼湿重(gbw)每周注射2次。化合物分别地应用于10只雄性罗非鱼(具有60.41±10.36g的平均体重)的组，和具有60.58±19.67g的平均体重的对照组仅接受作为对照的PBS，每周测量平均体重，该实验中的所有动物用微芯片(Stoelting Co.Wood Dale，USA.)进行标记以用于正确鉴定。在处理组中获得体重增加，具有相对于对照组而言165％的峰，如表5中所示。
表5.通过将对照组的生长作为100％而获得的以％表示的处理组的体重增加。
| 化合物 | 体重增加(％) | 化合物 | 体重增加(％) |
| A221 | 98.0 | A230 | 158.0 |
| A222 | 96.2 | A231 | 150.2 |
| A223 | 105.0 | A232 | 160.1 |
| A224 | 132.7 | A233 | 165.0 |
| A225 | 120.0 | A234 | 110.6 |
| A226 | 122.4 | A235 | 89.9 |
| A227 | 139.9 | A236 | 99.0 |
| A228 | 130.6 | A237 | 100.0 |
| A229 | 126.5 | A238 | 129.4 |
在相同实验中，研究了在该测定法中所使用的动物中单亲生殖的车轮虫和蠕虫的存在，以观察和比较致病体在处理组中侵袭的程度。表6显示了与未处理的动物的比较，所述未处理的动物显示出作为平均值的6个十字。
表6.在用所测化合物进行处理的动物中被病原体(车轮虫和蠕虫)感染的强度。
| 化合物 | 病原体 | 化合物 | 病原体 |
| A221 | +++++ | A230 | ++ |
| A222 | ++++ | A231 | ++ |
| A223 | ++++ | A232 | ++ |
| A224 | ++++ | A233 | ++ |
| A225 | ++++ | A234 | +++ |
| A226 | +++ | A235 | +++ |
| A227 | ++++ | A236 | ++++ |
| A228 | +++ | A237 | +++ |
| A229 | +++ | A238 | +++ |
5.2使用类似于肽性GHS的化合物通过浸浴对于罗非鱼(Oreochromis sp)幼体生长的刺激。
进行对罗非鱼(Oreochromis sp)幼体的生长刺激实验，评估了具有0.01g平均值的100条幼体的组，其中使用100μg/L的浓度的类似于肽性GHS的化合物，每周2次每次1小时的浸浴时间。如表7中所示，相对于接受PBS浸浴的对照组，在3周过程中获得155％的平均体重的最高生长刺激。
表7.通过将对照组的生长作为100％而获得的以％表示的处理组的体重增加。
| 化合物 | 体重增加(％) | 化合物 | 体重增加(％) |
| A221 | 97.0 | A230 | 150.0 |
| A222 | 96.0 | A231 | 151.0 |
| A223 | 102.0 | A232 | 148.3 |
| A224 | 130.0 | A233 | 155.0 |
| A225 | 98.0 | A234 | 120.6 |
| A226 | 120.4 | A235 | 90.0 |
| A227 | 140.6 | A236 | 105.0 |
| A228 | 132.0 | A237 | 109.9 |
| A229 | 125.0 | A238 | 112.6 |
在该实验期间还监控溶菌酶水平，并且在经处理的动物中获得这种免疫性标记的增加，如表8中所示。
表8.相对于对照组在经处理的动物中的溶菌酶水平。
| 化合物 | 溶菌酶 | 化合物 | 溶菌酶 |
| A221 | 1.01 | A230 | 1.33 |
| A222 | 1.43 | A231 | 1.89 |
| A223 | 1.52 | A232 | 2.41 |
| A224 | 1.37 | A233 | 2.68 |
| A225 | 1.43 | A234 | 2.77 |
| A226 | 1.17 | A235 | 1.90 |
| A227 | 1.52 | A236 | 1.42 |
| A228 | 1.08 | A237 | 1.01 |
| A229 | 1.15 | A238 | 1.33 |
实施例6：通过用类似于肽性GHS的化合物浸浴来进行的在凡纳滨对虾(Litopenaeus vanamei)中的生长实验。
虾幼体每3天用不同浓度的类似于肽性GHS的化合物浸浴1小时，进行4次。所使用的浓度为0.1mg/L，对照组以相同的浸浴频率用1mg/L BSA进行浸浴。
如表9中所示，结果观察到处理组中幼虫的品质得到改善，其具有120-150％的重量增长和10-25％的尺寸增加，还显示出更多的腮分枝和额部修饰(rostral modifications)。此外还发现，通常在处理组中动物具有较低的肌肉含水量和更佳的RNA/DNA、蛋白质/DNA值， 这显示在经处理的幼虫中具有更高的代谢激活。
表9.通过将对照组的生长作为100％而获得的以％表示的处理组的体重和尺寸增加。
| 化合物 | 体重增加(％)/ 尺寸增加(％) | 化合物 | 体重增加(％)/ 尺寸增加(％) |
| A221 | 120.1/112.0 | A230 | 150.0/123.6 |
| A222 | 121.0/112.2 | A231 | 130.0/123.0 |
| A223 | 120.0/110.9 | A232 | 132.8/123.0 |
| A224 | 127.0/116.0 | A233 | 143.0/124.9 |
| A225 | 121.0/112.6 | A234 | 123.6/114.2 |
| A226 | 120.1/112.2 | A235 | 121.0/112.5 |
| A227 | 128.6/118.5 | A236 | 121.0/112.0 |
| A228 | 128.2/118.9 | A237 | 127.0/116.2 |
| A229 | 126.1/115.9 | A238 | 129.2/117.9 |
该实验还在化合物A221、A228和A233的产生条件下进行确证，与对照相比较在经处理的动物中存活增加20％，此外保持在体重方面110％和在尺寸方面30％的平均刺激，显示出在经处理的动物中具有在尺寸分布方面更佳的同质性，在体重和尺寸方面分别仅30％和8％的变异系数，这与未处理组中的77％和30％形成明显不同。
实施例7：通过在饮食中包括类似于肽性GHS的化合物来刺激虾的生长。
将类似于肽性GHS的化合物以1％包括在甲壳类后期幼体饮食中。给凡纳滨对虾的后期幼体饲喂上述饮食，并且平行地使用在饲喂中包括了1％BSA的对照组。通过下述方式来评测效应：用光学测微计测量幼体和后期幼体的甲壳的长度，并且以0.1mg的误差对动物进行称重。
如表10中所示，与对照组相比较，所添加的化合物产生30-40％的尺寸增加。
表10.通过将对照组的生长作为100％而获得的以％表示的处理组的尺寸增加。
| 化合物 | 尺寸增加(％) | 化合物 | 尺寸增加(％) |
| A221 | 130.0 | A230 | 140.0 |
| A222 | 131.0 | A231 | 140.1 |
| A223 | 131.6 | A232 | 139.7 |
| A224 | 131.2 | A233 | 140.1 |
| A225 | 130.0 | A234 | 138.6 |
| A226 | 130.4 | A235 | 137.0 |
| A227 | 139.0 | A236 | 137.0 |
| A228 | 140.0 | A237 | 132.0 |
| A229 | 140.0 | A238 | 130.1 |
7.1：盐生丰年虫(Artemia salina)封装
将类似于肽性GHS的化合物生物封装在卤虫中以饲喂给凡纳滨对虾后期幼体。为了进行封装，以10mg/L添加所述化合物，静置1小时，收获，并洗涤。动物每天饲喂四次，持续1个月，而对照组用具有经封装的BSA的卤虫进行饲喂。通过下述方式来评测所述化合物的效应：用光学测微计测量幼体和后期幼体的甲壳的长度，并且以0.01mg的误差对动物进行称重。
如表11中所示，封装在盐生丰年虫中的化合物使动物的生长相对于对照组增加30％-40％，具有高度显著差异(p<0.001)。
表11.通过将对照组的生长作为100％而获得的以％表示的处理组的尺寸增加。
| 化合物 | 尺寸增加(％) | 化合物 | 尺寸增加(％) |
| A221 | 130.2 | A230 | 140.0 |
| A222 | 130.3 | A231 | 140.2 |
| A223 | 132.0 | A232 | 139.6 |
| A224 | 130.0 | A233 | 140.0 |
| A225 | 130.0 | A234 | 135.0 |
| A226 | 132.0 | A235 | 134.2 |
| A227 | 140.0 | A236 | 138.0 |
| A228 | 140.0 | A237 | 136.0 |
| A229 | 140.0 | A238 | 140.0 |
实施例8：在大鼠中类似于肽性GHS的化合物的心脏保护效应。
为了重现扩张型心肌病(Dilated Cardiomyopathy，DCM)的病理生理学效应，在8周期间用2mg/kg多柔比星(Dx)处理160g的雌性Wistar大鼠。在8周的Dx处理期间这组大鼠还平行地用化合物A221、A228或A233以500μg/Kg经腹膜内途径进行处理，另一个Dx处理组还接受盐水溶液作为安慰剂，并且使用另一组相同年龄的未处理的Wistar大鼠作为实验的健康对照。8周处理后，所有大鼠用超声心动图进行测试，以测试心室功能性并评估心室射血分数(ventricular ejection fraction，VEF)。如图1中所示，相对于健康对照，接受平行的Dx-化合物A221(1a)、A228(1b)或A233(1c)的大鼠显示出略微改变的VEF(p>0.05)，相比之下，接受安慰剂的组相对于健康对照组而言VEF下降大约40％(p<0.01)。为了从牵涉VEF下降的功能观点来证实DCM的影响以及在应激应答中出现的反响，对大鼠实施在4℃水中30分钟的强迫游泳。如图2中所示，接受使用Dx-化合物A221(2a)、A228(2b)或A233(2c)进行处理的动物具有100％的存活，和经Dx-盐水溶液处理的动物仅有45％存活(p＝0.0043)。这个结果暗示，由化合物A221、A228和A233引起的保护作用不仅维持了VEF，而且还产生了对于强迫应激具有抵抗力的心脏。
实施例9：在大鼠中类似于肽性GHS的化合物对于扩张型心肌病(DCM)的心脏保护效应和逆转。
为了评估是否存在任何剂量-反应效应和DCM的逆转，对Wistar大鼠实施共8周的使用2mg/kg多柔比星(Dx)的处理，在处理后，选择出具有高于40％的VEF下降的所有大鼠，分成n＝8的组，并且如下用不同剂量的化合物A221、A228或A233进行处理：
·500μg/kg，
·250μg/kg，
·100μg/kg，
·50μg/kg，
·25μg/kg，
·10μg/kg，
·盐水溶液。
基于A221剂量来定义组。
如图3中所示，在以50μg/kg-500μg/kg的浓度范围用化合物A221(3a)、A228(3b)或A233(3c)进行2周的处理后部分逆转了DCM，但在进行4周的处理时，在接受100-500μg/kg的化合物A221、A228或A233的组中完全逆转了DCM。相对于接受安慰剂的动物或用较低浓度处理的组(这些动物不恢复VEF并在处理结束后具有较低的存活天数)，50μg/kg的剂量对于VEF的总体恢复无效，但对于减少组中的死亡率在一定程度上有效。(图4，a：A221；b：A228；和c：A233)。
本发明还涉及如下的9个项目：
1.具有内部环和L-氨基酸的肽性质化学分子，其能够发挥与生长激素肽性促分泌素相似的功能，其中所述肽性质化学分子由标示为Seq ID No.13的序列的氨基酸序列组成。
2.药物组合物，其包含根据项目1的肽性质化学分子或其药学上可接受的盐，以及赋形剂或载体。
3.根据项目2的药物组合物，其特征在于，当所述药物组合物为溶液或冻干粉末时，所述药物组合物具有2-100μg/ml的所述肽性质化学分子。
4.用于水产养殖或者其他的动物饲养的兽医学组合物，其包含根据项目1的肽性质化学分子或其兽医学上可接受的盐，以及赋形剂或载体。
5.根据项目4的兽医学组合物，其特征在于，所述组合物是饲料、营养补充剂、定期注射或浸浴的形式，且所述兽医学组合物能够在鱼类或甲壳类中刺激生长和/或增强抗病能力。
6.根据项目1的肽性质化学分子或其药学上可接受的盐在制备药物组合物中的用途，所述药物组合物用于在有此需要的患者中诱导生长激素释放。
7.根据项目1的肽性质化学分子或其药学上可接受的盐在制备药物组合物中的用途，所述药物组合物用于在有此需要的患者中诱导心脏保护和/或神经保护和/或食欲的控制和调节，所述食欲的控制和调节包括脂肪和能量代谢的调节。
8.根据项目1的肽性质化学分子或其药学上可接受的盐在制备兽医学组合物中的用途，所述兽医学组合物用于在鱼类或甲壳类中刺激生长和/或增强抗病能力。
9.根据项目8的的用途，其中，当作为用于食物供给的饲料进行施用时，所述项目1的肽性质化学分子处于0.01-1％的范围内；当以定期注射进行施用时，所述项目1的肽性质化学分子处于0.05-10μg/克动物湿重的范围内；或当以浸浴进行施用时，所述项目1的肽性质化学分子处于10-500μg/L的范围内。
序列表
<110>CENTER FOR GENETIC ENGINEERING AND BIOTECHNOLOGY
<120>类似于生长激素的肽性促分泌素的化合物以及包含其的制剂
<130>ACUABI05
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<150>CU 2006-0050
<151>2006-02-28
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<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys3和Asp5的侧链上。
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<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys3和Asp5的侧链上。
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<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Asp3和Lys5的侧链上。
<400>4
Ser Ser Asp Phe Lys Leu Tyr Trp Gly
1 5
<210>5
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Asp3和Lys5的侧链上。
<400>5
Ala Leu Asp Phe Lys Pro Asn Ile Pro
1 5
<210>6
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Asp3和Lys5的侧链上。
<400>6
Ala Leu Asp Phe Lys Pro Asn Ile Pro
1 5
<210>7
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys3和Asp6的侧链上。
<400>7
His Ser Lys Gly Tyr Asp Leu Asp His
1 5
<210>8
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys2和Asp5的侧链上。
<400>8
Gly Lys Phe Gly Asp Leu Ser Pro Glu His Gln
1 5 10
<210>9
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys3和Asp8的侧链上。
<400>9
His Ala Lys Pro Gly Gly Ile Asp Pro Glu Gln
1 5 10
<210>10
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys2和Asp4的侧链上。
<400>10
Gly Lys Phe Asp Ser Pro Glu His Gln
1 5
<210>11
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys4和Asp7的侧链上。
<400>11
Gly Gly Gly Lys Phe Trp Asp Ile Pro His His
1 5 10
<210>12
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys2和Asp5的侧链上。
<400>12
His Lys Gly Ile Asp Ser Pro Glu Gln His
1 5 10
<210>13
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Lys2和Asp4的侧链上。
<400>13
Gly Lys Phe Asp Leu Ser Pro Glu His Gln
1 5 10
<210>14
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Asp2和Lys6的侧链上。
<400>14
Gly Asp Ala Gly Ala Lys Leu Leu Ser Ser Arg
1 5 10
<210>15
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Glu3和Lys7的侧链上。
<400>15
Gly Met Glu Ala Gly Ile Lys Leu Cys His Arg Gln
1 5 10
<210>16
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Glu2和Lys5的侧链上。
<400>16
Gly Glu Gly Tyr Lys Leu Asp Glu Arg Ser Gln
1 5 10
<210>17
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Glu3和Lys6的侧链上。
<400>17
Gly Gly Glu Ala Gly Lys Leu Cys Pro Pro Arg Tyr
1 5 10
<210>18
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述：符合本专利中描述的结构规律性的具有内部环的示例性肽序列。
环处于Glu3和Lys5的侧链上。
<400>18
Gly Leu Glu Phe Lys Leu Leu His Gln
1 5
Claims (9)
1.具有内部环和L-氨基酸的肽性质化学分子，其能够发挥与生长激素肽性促分泌素相似的功能，其中所述肽性质化学分子由标示为SeqID No.13的序列的氨基酸序列组成。
2.药物组合物，其包含根据权利要求1的肽性质化学分子或其药学上可接受的盐，以及赋形剂或载体。
3.根据权利要求2的药物组合物，其特征在于，当所述药物组合物为溶液或冻干粉末时，所述药物组合物具有2-100μg/ml的所述肽性质化学分子。
4.用于水产养殖或者其他的动物饲养的兽医学组合物，其包含根据权利要求1的肽性质化学分子或其兽医学上可接受的盐，以及赋形剂或载体。
5.根据权利要求4的兽医学组合物，其特征在于，所述组合物是饲料、营养补充剂、定期注射或浸浴的形式，且所述兽医学组合物能够在鱼类或甲壳类中刺激生长和/或增强抗病能力。
6.根据权利要求1的肽性质化学分子或其药学上可接受的盐在制备药物组合物中的用途，所述药物组合物用于在有此需要的患者中诱导生长激素释放。
7.根据权利要求1的肽性质化学分子或其药学上可接受的盐在制备药物组合物中的用途，所述药物组合物用于在有此需要的患者中诱导心脏保护和/或神经保护和/或食欲的控制和调节，所述食欲的控制和调节包括脂肪和能量代谢的调节。
8.根据权利要求1的肽性质化学分子或其药学上可接受的盐在制备兽医学组合物中的用途，所述兽医学组合物用于在鱼类或甲壳类中刺激生长和/或增强抗病能力。
9.根据权利要求8的的用途，其中，当作为用于食物供给的饲料进行施用时，所述权利要求1的肽性质化学分子处于0.01-1％的范围内；当以定期注射进行施用时，所述权利要求1的肽性质化学分子处于0.05-10μg/克动物湿重的范围内；或当以浸浴进行施用时，所述权利要求1的肽性质化学分子处于10-500μg/L的范围内。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CU2006-0050 | 2006-02-28 | ||
| CU20060050A CU23558A1 (es) | 2006-02-28 | 2006-02-28 | Compuestos análogos a los secretagogos peptidicos de la hormona de crecimiento |
| CU20060050 | 2006-02-28 | ||
| PCT/CU2007/000007 WO2007098716A1 (es) | 2006-02-28 | 2007-02-28 | Compuestos analogos a los secretagogos peptidicos de la hormona de crecimiento y preparaciones que los contienen |
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| CN101432294A CN101432294A (zh) | 2009-05-13 |
| CN101432294B true CN101432294B (zh) | 2013-09-11 |
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| CN2007800153594A Expired - Fee Related CN101432294B (zh) | 2006-02-28 | 2007-02-28 | 类似于生长激素的肽性促分泌素的化合物以及包含其的制剂及用途 |
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| US (1) | US8367620B2 (zh) |
| EP (1) | EP1997827B1 (zh) |
| JP (1) | JP5183496B2 (zh) |
| KR (1) | KR101409277B1 (zh) |
| CN (1) | CN101432294B (zh) |
| AR (1) | AR059646A1 (zh) |
| AU (1) | AU2007219569B2 (zh) |
| BR (1) | BRPI0708366A2 (zh) |
| CA (1) | CA2637593C (zh) |
| CL (2) | CL2007000528A1 (zh) |
| CU (1) | CU23558A1 (zh) |
| ES (1) | ES2441441T3 (zh) |
| MX (1) | MX2008011142A (zh) |
| MY (1) | MY184130A (zh) |
| NO (1) | NO20084118L (zh) |
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| JP4831551B2 (ja) * | 2008-11-06 | 2011-12-07 | 国立大学法人名古屋大学 | 非虚血性心筋障害に対する医薬 |
| CU24473B1 (es) * | 2016-11-01 | 2020-02-04 | Centro De Ingenieria Genetica Y Biotecnologia Biocubafarma | Composición vacunal que comprende un péptido secretagogo de la hormona de crecimiento como adyuvante vacunal |
| RU2734835C1 (ru) * | 2020-02-11 | 2020-10-23 | Федеральное государственное бюджетное учреждение науки Лимнологический институт Сибирского отделение Российской академии наук (ЛИН СО РАН) | Способ повышения жизнестойкости эмбрионов рыб в аквакультуре |
Family Cites Families (92)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3239345A (en) | 1965-02-15 | 1966-03-08 | Estrogenic compounds and animal growth promoters | |
| US4411890A (en) | 1981-04-14 | 1983-10-25 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4036979A (en) | 1974-01-25 | 1977-07-19 | American Cyanamid Company | Compositions containing 4,5,6,7-tetrahydrobenz[b]thien-4-yl-ureas or derivatives and methods of enhancing growth rate |
| DE68922602T2 (de) | 1988-01-28 | 1995-12-07 | Polygen Holding Corp | Polypeptide mit hormonwachstumsbefreiender wirkung. |
| JPH03502326A (ja) | 1988-01-28 | 1991-05-30 | ポリゲン ホールディング コーポレイション | 成長ホルモン放出活性を有するポリペプチド化合物類 |
| JP2670680B2 (ja) | 1988-02-24 | 1997-10-29 | 株式会社ビーエムジー | 生理活性物質含有ポリ乳酸系微小球およびその製造法 |
| WO1992007578A1 (en) | 1990-10-25 | 1992-05-14 | Genentech, Inc. | Use of protective agents against reactive oxygen species |
| US5663146A (en) | 1991-08-22 | 1997-09-02 | Administrators Of The Tulane Educational Fund | Polypeptide analogues having growth hormone releasing activity |
| WO1994011012A1 (en) | 1992-11-06 | 1994-05-26 | Merck & Co., Inc. | Substituted dipeptide analogs promote release of growth hormone |
| US5726319A (en) | 1992-11-06 | 1998-03-10 | Merck & Co., Inc. | Biphenyl substituted dipeptide analogs promote release of growth hormone |
| CZ151495A3 (en) | 1992-12-11 | 1995-12-13 | Merck & Co Inc | Spiropiperidine derivatives, process of their preparation and a pharmaceutical composition containing thereof |
| US5536716A (en) | 1992-12-11 | 1996-07-16 | Merck & Co., Inc. | Spiro piperidines and homologs which promote release of growth hormone |
| BR9407869A (pt) | 1993-10-19 | 1996-10-29 | Merck & Co Inc | Combinaçao composiçao farmacêutica e processo para o tratamento de osteoporose |
| US5492916A (en) | 1993-12-23 | 1996-02-20 | Merck & Co., Inc. | Di- and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
| US5494919A (en) | 1993-11-09 | 1996-02-27 | Merck & Co., Inc. | 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
| AU1172995A (en) | 1993-11-09 | 1995-05-29 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| AU684878B2 (en) | 1993-11-24 | 1998-01-08 | Merck & Co., Inc. | Compounds and the use thereof to promote the release of growth hormone(s) |
| US5721251A (en) | 1993-12-10 | 1998-02-24 | Merck & Co., Inc. | Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone |
| US5721250A (en) | 1993-12-23 | 1998-02-24 | Merck & Co. Inc. | Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
| HU221092B1 (en) | 1993-12-23 | 2002-08-28 | Novo Nordisk As | Compounds with growth hormone releasing properties |
| UA42747C2 (uk) | 1993-12-23 | 2001-11-15 | Ново Нордіск А/С | Похідні пептиду,фармацевтична композиція та спосіб стимулювання секреції гормону росту |
| WO1995034311A1 (en) | 1994-06-13 | 1995-12-21 | Merck & Co., Inc. | Piperazine compounds promote release of growth hormone |
| US5783582A (en) | 1994-07-20 | 1998-07-21 | Merck & Co., Inc. | Piperidines and hexahydro-1H-azepines spiro substituted at the 4-position promote release of growth hormone |
| US5798337A (en) | 1994-11-16 | 1998-08-25 | Genentech, Inc. | Low molecular weight peptidomimetic growth hormone secretagogues |
| WO1996022996A1 (fr) | 1995-01-25 | 1996-08-01 | Nippon Chemiphar Co., Ltd. | Derives de dihydrophenazine |
| MX9705710A (es) | 1995-01-27 | 1997-10-31 | Novo Nordisk As | Compuestos con propiedades de liberacion de la hormona del crecimiento. |
| WO1996024587A1 (en) | 1995-02-09 | 1996-08-15 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| AU4534596A (en) | 1995-02-09 | 1996-08-27 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| US5559128A (en) | 1995-04-18 | 1996-09-24 | Merck & Co., Inc. | 3-substituted piperidines promote release of growth hormone |
| WO1996033189A1 (en) | 1995-04-19 | 1996-10-24 | Merck & Co., Inc. | Process for the preparation of spiroindolines |
| WO1996035713A1 (en) | 1995-05-08 | 1996-11-14 | Pfizer, Inc. | Dipeptides which promote release of growth hormone |
| EP0828754B1 (en) | 1995-05-29 | 2005-02-02 | Pfizer Inc. | Dipeptides which promote release of growth hormone |
| HUP9802821A3 (en) | 1995-06-22 | 2000-03-28 | Novo Nordisk As | Compounds with growth hormone releasing properties |
| ZA966891B (en) | 1995-08-21 | 1998-02-16 | Lilly Co Eli | 2-acylaminopropanamines as growth hormone secretagogues. |
| AU6772996A (en) | 1995-08-21 | 1997-03-12 | Eli Lilly And Company | 2-acylaminopropanamides as growth hormone secretagogues |
| EP0766966A3 (en) | 1995-09-08 | 2001-02-28 | Eli Lilly And Company | Method of treating insulin resistance |
| AU7169696A (en) | 1995-09-26 | 1997-04-17 | Merck & Co., Inc. | 3-spirolactam, 3-spiroamino, 3-spirolactone and 3-spirobenzopyran piperidines and pyrrolidines promote release of growth hormone |
| EA199800337A1 (ru) | 1995-10-27 | 1998-10-29 | Мерк Энд Ко., Инк. | Способ получения гормона роста, усиливающего секрецию |
| US5767124A (en) | 1995-10-27 | 1998-06-16 | Merck & Co., Inc. | Polymorphic forms of a growth hormone secretagogue |
| CA2235511A1 (en) | 1995-10-27 | 1997-05-01 | Merck & Co., Inc. | Process for the preparation of a growth hormone secretagogue |
| WO1997015191A1 (en) | 1995-10-27 | 1997-05-01 | Merck & Co., Inc. | Wet granulation formulation of a growth hormone secretagogue |
| ATE334394T1 (de) | 1995-12-13 | 2006-08-15 | Merck & Co Inc | Testverfahren für die sekretionsrezeptoren von wachstumshormonen |
| ATE279440T1 (de) | 1995-12-13 | 2004-10-15 | Merck & Co Inc | Wachstumshormonsekretionsförderer rezeptorfamilie |
| IT1277113B1 (it) | 1995-12-20 | 1997-11-04 | Romano Deghenghi | Composti oligopeptidici contenenti d-2-alchiltriptofano in grado di promuovere la liberazione dell'ormone della crescita |
| WO1997022367A1 (en) | 1995-12-20 | 1997-06-26 | Merck & Co., Inc. | Radiolabeled growth hormone secretagogue |
| ES2323159T3 (es) | 1995-12-22 | 2009-07-07 | Novo Nordisk A/S | Compuestos con propiedades de liberacion de la hormona del crecimiento. |
| TW432073B (en) | 1995-12-28 | 2001-05-01 | Pfizer | Pyrazolopyridine compounds |
| AU2334097A (en) | 1996-03-21 | 1997-10-10 | Merck & Co., Inc. | 4-spiroindoline piperidines promote release of growth hormone |
| WO1997036873A1 (en) | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| SE9601397D0 (sv) | 1996-04-12 | 1996-04-12 | Pharmacia Ab | Use of growth hormone |
| JP2000510453A (ja) | 1996-04-19 | 2000-08-15 | ノボ ノルディスク アクティーゼルスカブ | 成長ホルモン遊離特性を有する化合物 |
| CN1127488C (zh) | 1996-04-24 | 2003-11-12 | 诺沃挪第克公司 | 具有生长激素释放特性的化合物 |
| US5919777A (en) | 1996-04-24 | 1999-07-06 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| WO1997041878A1 (en) | 1996-05-07 | 1997-11-13 | Merck & Co., Inc. | Treatment of mood disorders with a growth hormone secretagogue |
| EP0900086A4 (en) | 1996-05-07 | 2000-01-12 | Merck & Co Inc | IMPROVING THE SLEEP BY MEANS OF A SUBSTANCE PROMOTING THE SECRETION OF GROWTH HORMONES |
| AU2764797A (en) | 1996-05-14 | 1997-12-05 | Novo Nordisk A/S | Somatostatin agonists and antagonists |
| WO1997044042A1 (en) | 1996-05-22 | 1997-11-27 | Arch Development Corporation | Sleep quality improvement using a growth hormone secretagogue |
| KR20000016204A (ko) | 1996-05-31 | 2000-03-25 | 한센 핀 베네드, 안네 제헤르 | 골다공증의 주기적(연계) 치료에 있어 성장호르몬 성분 및 뼈의항흡수 약물 |
| AU3434697A (en) | 1996-07-22 | 1998-02-10 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| WO1998010653A1 (en) | 1996-09-13 | 1998-03-19 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| WO1998018815A1 (en) | 1996-10-25 | 1998-05-07 | Merck & Co., Inc. | Convergent process for the preparation of a growth hormone secretagogue |
| SE9703929D0 (sv) | 1996-11-22 | 1997-10-28 | Pharmacia & Upjohn Ab | Therapeutical use and method |
| AU6747498A (en) | 1997-04-11 | 1998-11-11 | Sumitomo Pharmaceuticals Company, Limited | Benzene derivatives |
| JP2000514838A (ja) | 1997-05-14 | 2000-11-07 | 藤沢薬品工業株式会社 | 成長ホルモンの放出を促進するピペリジノ誘導体 |
| US5861149A (en) | 1997-06-04 | 1999-01-19 | Polyheal Ltd. | Methods for wound treatment |
| AU7906998A (en) | 1997-06-20 | 1999-01-04 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| JP3514774B2 (ja) | 1997-06-25 | 2004-03-31 | ファイザー・インク | 成長ホルモン分泌促進薬としてのジペプチド誘導体 |
| UA64751C2 (uk) | 1997-06-25 | 2004-03-15 | Пфайзер Продактс Інк. | Спосіб лікування інсулінової толерантності речовинами, які посилюють секрецію гормону росту (варіанти) та фармацевтична композиція (варіанти) |
| UA53716C2 (uk) | 1997-06-25 | 2003-02-17 | Пфайзер Продактс Інк. | Тартратна сіль заміщеного дипептиду, спосіб її одержання, проміжні сполуки та спосіб їх одержання, фармацевтична композиція (варіанти), спосіб підвищення рівнів ендогенного гормону росту та спосіб лікування або профілактики захворювань (варіанти) |
| ZA987383B (en) | 1997-08-19 | 2000-02-17 | Lilly Co Eli | Treatment of congestive heart failure with growth hormone secretagogues. |
| DE69836386T2 (de) | 1997-08-22 | 2007-10-11 | Kaken Pharmaceutical Co., Ltd. | Amide zur Förderung der Ausschüttung von Wachstumshormonen |
| EP1506969B1 (en) | 1998-01-16 | 2010-06-09 | Helsinn Therapeutics (U.S.), Inc. | Compounds with growth hormone releasing properties |
| WO1999039730A1 (fr) | 1998-02-09 | 1999-08-12 | Kaken Pharmaceutical Co., Ltd. | Preparation a administration orale contenant des peptides favorisant la secretion d'hormone de croissance |
| CN1291994A (zh) | 1998-03-03 | 2001-04-18 | 诺沃挪第克公司 | 新的(2e)－5－氨基－5－甲基已－2－烯酸n－甲基－n－((1r)－1－(n－甲基－n－(1r)－1－(甲基氨基甲酰基)－2－苯2基氨基甲酰基－2－(2－萘基)2基酰胺的盐 |
| PL194560B1 (pl) | 1998-05-11 | 2007-06-29 | Novo Nordisk As | Związki o właściwościach uwalniania hormonu wzrostu, kompozycja farmaceutyczna zawierająca te związki oraz ich zastosowanie |
| JP4574849B2 (ja) | 1998-06-09 | 2010-11-04 | サファイア セラピューティクス，インコーポレイティド | 成長ホルモン放出特性を有する化合物を調製するための方法 |
| CN1305378A (zh) | 1998-06-16 | 2001-07-25 | 辉瑞产品公司 | 治疗肌与骨骼的脆性的(选择性)雌激素受体调节剂(serm)和生长激素促分泌素(ghs)的药物组合物 |
| PA8475901A1 (es) | 1998-06-16 | 2000-05-24 | Pfizer Prod Inc | Terapia de combinacion para la fragilidad musculoesqueletica |
| WO2000001726A1 (en) | 1998-06-30 | 2000-01-13 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| AU5301199A (en) | 1998-08-20 | 2000-03-14 | Sumitomo Pharmaceuticals Company, Limited | Oxindole derivatives as growth hormone releasers |
| US6358951B1 (en) | 1998-08-21 | 2002-03-19 | Pfizer Inc. | Growth hormone secretagogues |
| US6849597B2 (en) | 1999-12-28 | 2005-02-01 | Kaken Pharmaceutical Co., Ltd. | Neuroprotective drug |
| US6967237B2 (en) | 2000-05-30 | 2005-11-22 | Merck & Co., Inc. | Ghrelin analogs |
| ES2333097T3 (es) | 2000-05-31 | 2010-02-17 | Raqualia Pharma Inc | Uso de secretagogos de la hormona de crecimiento para estimular la motilidad gastrointestinal. |
| ATE302181T1 (de) | 2000-06-13 | 2005-09-15 | Zentaris Gmbh | Verbindungen zur stimulation der sekretion von wachstumshormonen |
| WO2001097831A1 (fr) | 2000-06-23 | 2001-12-27 | Kaken Pharmaceutical Co., Ltd. | Agents therapeutiques et prophylactiques destines a l'insuffisance cardiaque |
| ITMI20011445A1 (it) | 2001-07-06 | 2003-01-06 | Europ Geie | Analoghi della cortistantina capaci di legarsi selettivamente ai recettori dei secretagoghi dell'ormone della crescita |
| HK1077740A1 (en) | 2001-12-20 | 2006-02-24 | Ct Ingenieria Genetica Biotech | Use of epidermal growth factor in the manufacture of a pharmaceutical injection composition for preventing diabetic limb amputation |
| US7476653B2 (en) | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
| WO2005039625A1 (en) | 2003-10-28 | 2005-05-06 | Rheoscience A/S | Growth hormone secretagogue receptor agonists |
| US7504506B2 (en) | 2003-11-04 | 2009-03-17 | Elixir Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| WO2005048916A2 (en) | 2003-11-20 | 2005-06-02 | Biovitrum Ab | Tetrahydrospiro-beta-carboline-1,3 '-pyrrolidine derivatives and their use in ghsr-related disorders |
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Non-Patent Citations (2)
| Title |
|---|
| B. Lammek et al.Synthesis of three NH2-terminally extended arginine-vasopressins with prolonged biological activities.《Experientia》.1987,第43卷1211-1212. * |
| J.H. Cort et al.Regional and Systemic Haemodynamic Effects of Some Vasopressins:Structural Features of the Hormone which Prolong Activity.《Europ.J.clin.1nvest.》.1975,第5卷165-175. * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101409277B1 (ko) | 2014-06-24 |
| CU23558A1 (es) | 2010-07-20 |
| CN101432294A (zh) | 2009-05-13 |
| CA2637593C (en) | 2015-04-14 |
| CL2016001648A1 (es) | 2017-02-24 |
| BRPI0708366A2 (pt) | 2011-05-24 |
| WO2007098716A8 (es) | 2008-12-18 |
| KR20080110763A (ko) | 2008-12-19 |
| US8367620B2 (en) | 2013-02-05 |
| EP1997827A1 (en) | 2008-12-03 |
| CL2007000528A1 (es) | 2008-01-18 |
| AR059646A1 (es) | 2008-04-16 |
| EP1997827B1 (en) | 2013-10-09 |
| ES2441441T3 (es) | 2014-02-04 |
| RU2008138569A (ru) | 2010-04-10 |
| US20100055118A1 (en) | 2010-03-04 |
| NO20084118L (no) | 2008-09-29 |
| MX2008011142A (es) | 2008-09-08 |
| JP2009528303A (ja) | 2009-08-06 |
| MY184130A (en) | 2021-03-19 |
| RU2416618C2 (ru) | 2011-04-20 |
| JP5183496B2 (ja) | 2013-04-17 |
| CA2637593A1 (en) | 2007-09-07 |
| AU2007219569B2 (en) | 2012-03-15 |
| WO2007098716A1 (es) | 2007-09-07 |
| ZA200807162B (en) | 2009-06-24 |
| AU2007219569A1 (en) | 2007-09-07 |
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