CN1594358A - 通过给予生长激素释放化合物或其拮抗剂来治疗肿瘤 - Google Patents
通过给予生长激素释放化合物或其拮抗剂来治疗肿瘤 Download PDFInfo
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Abstract
治疗哺乳动物体内肿瘤的方法，所述的方法包括给予有效剂量的生长激素释放肽或其拮抗剂以降低或抑制肿瘤发生细胞在哺乳动物体内的增殖。特别地，所治疗的肿瘤为肺肿瘤、乳腺肿瘤、甲状腺肿瘤或胰腺肿瘤。优选的化合物是一些含有甲基色氨酸和赖氨酸单位的肽类。
Description
本申请是申请日为1999年11月11日、申请号为99813361.2、发明名称为“通过给予生长激素释放化合物或其拮抗剂来治疗肿瘤”的中国发明专利申请的分案申请。
本发明涉及通过给予生长激素释放肽或其拮抗剂来降低肿瘤细胞增殖的方法。
生长激素(GH)的分泌由两类下丘脑肽调节：GH-释放激素(GHRH)，其对生长激素的释放具有刺激作用，以及生长激素释放抑制因子，其对生长激素的释放具有抑制作用。在过去的几年中，几种研究证明GH的分泌还可受到合成低聚肽(又称GH-释放肽(GHRP))的刺激，例如海噻瑞林(Hexarelin)及各种海噻瑞林的类似物(Ghigo等人，EuropeanJournal of Endocrinology，136，445-460，1997)。这些化合物通过与GHRH明显不同的机理发挥作用(C.Y.Bowers，“异种生物生长激素促分泌素”，Eds.B.Bercu和R.F.Walker，pg.9-28，Springer-Verlag，NewYork 1996)并且与位于下丘脑的特异性受体及垂体腺体具有相互作用((a)G.Muccioli等人，Journal of Endocrinology，157，99-106，1998；(b)G.Muccioli，“GHRP受体在人体中的组织分布”，Abstracts IVEuropean Congress of Endocrinology，Sevilla，Spain，1998)。最近证明GHRP受体不仅存在于下丘脑-垂体系统中，而且甚至存在于各种通常与GH释放无关的人类组织中(G.Muccioli等人，参见上文(a))。
在下列出版物中描述了GHRPs及其拮抗剂：C.Y.Bowers，Supra，R.Deghenghi，“生长激素释放肽”，Ibidem，1996，pg.85-102；R.Deghenghi等人，“作为生长激素强释放剂的小分子肽”，J.Ped.End.Metab.，8，pg.311-313，1996；R.Deghenghi，“作为生长激素促分泌素的不可透过肽类的发展”，Acta Paeditr.Suppl.，423，pg.85-87，1997；K.Veeraraganavan等人，“与猪前垂体和下丘脑膜有关的生长激素释放肽(GHRP)”，Life Sci.，50，pg.1149-1155，1992；及T.C.Somers等人，“低分子量的仿肽生长激素促分泌素”，WO 96/15148(1996年5月23日)。
本发明涉及治疗哺乳动物体内肿瘤的方法，所述的方法包括给予需要治疗的哺乳动物治疗有效剂量的生长激素释放肽(GHRP)或其拮抗剂。另外根据本发明，所用的化合物可以定义为生长激素促分泌素或其拮抗剂。所用化合物的量可有效地降低或抑制哺乳动物体内肿瘤发生细胞的增殖。在另一个实施方案中，这些化合物被赋予了如下特征：即它们从哺乳动物含肿瘤的组织中取代了放射活性标记物125I-Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2(125I-Tyr-Ala-海噻瑞林)。
这里所公开的化合物显示了与肿瘤发生组织的结合，并且已经发现它们能在给药后象特异性的受体一样发挥作用，从而使得肿瘤发生细胞的数量有所降低。优选地，所治疗的肿瘤为肺肿瘤、乳腺肿瘤、甲状腺肿瘤或胰腺肿瘤。
上述提到的化合物包括一些已知的化合物(参见上文)，但其它用于本发明的化合物是以前未公开的，包括螺旋内酰胺、双环或三环仿肽单位。本发明所用所有化合物一个共同的特征是至少存在一个赖氨酸单位。
在此描述中，使用了下列缩写：D为右旋对映体，GH为生长激素，Mrp为2-甲基-Trp，IMA为咪唑基乙酰基，GAB为γ-氨基丁酰基，INIP为isopecotinyl，AIB为氨基异丁酰基，Nal为β-萘基丙氨酸，TXM为tranexamyl，即4-(氨基甲基)-环己基羰基，D-HNH为D-1，2，3，4，5，6-六氢-降哈尔满(norharman)-3-羧酸酯(盐)，HAIC为(2S，5S)-5-氨基-1，2，4，5，6，7-六氢-氮杂并[3，2，1-hi]吲哚-4-酮-2-羧酸酯(盐)，ATAB为2-R-(2β，5β，8β)-8-氨基-7-氧-4-硫杂-1-氮杂-双环[3.4.0]壬烷-2-羧酸酯(盐)，并且Ala、Lys、Phe、Trp、His、Thr、Cys、Thr、Leu和Ile分别代表丙氨酸、赖氨酸、苯丙氨酸、色氨酸、组氨酸、苏氨酸、半胱氨酸、酪氨酸、亮氨酸和异亮氨酸。
在本发明优选的实施方案中，所给予的有用化合物具有下列通式I：
AA1-AA2-AA3-AA4-Lys-R (I)
其中
AA1为IMA，GAB，INIP，TXM，AIB，HIs-D-Trp-，His-D-Mrp，
Thr-D-Trp，
Thr-D-Mrp，D-Thr-D-Trp，D-Thr-D-Mrp，D-Ala-D-Nal，IMA-D-
Trp，IMA-D-Mrp，
D-Thr-His-D-Trp，D-Thr-His-D-Mrp，Cys-Tyr-GAB，Ala-His-
Trp，
Ala-His-D-Mrp，Tyr-Ala-His-D-Trp，Tyr-Ala-His-D-Mrp，D-
Ala-D-Trp，
或D-Ala-D-Mrp；
AA2为Ala，D-Nal，D-Lys，D-Mrp，或Trp；
AA3为D-Trp，D-Nal，D-Trp，Mrp，D-Mrp、Phe，或D-Phe；
AA4为D-Trp，Mrp，D-Mrp，Phe，或D-Phe；和
R为-NH2，Thr-NH2，或D-Thr-NH2。
含有D-Mrp单位的化合物是优选的。
在另一个实施方案中，有用的化合物包括那些在U.S.权利申请No.09/089,954(1998年6月3日申请)中所述的化合物。这些化合物是具有通式II的肽类化合物：
A-B-D-Mrp-C-D (II)
其中
A为H或Tyr；
B为具通式III的螺内酰胺
其中的R1为H或Tyr，R2为任意一个天然存在的氨基酸侧链，*处的构型为(R)，(S)或其混合物；式IV三环化合物
其中的R3为H或Tyr，*处的构型为(R)，(S)或其混合物；式V双环化合物
其中的R4为H或Tyr，*处的构型为(R)，(S)或其混合物；
D-Mrp为右旋-2-甲基-Trp；
C为
Trp-Phe-Lys，D-Trp-Phe-Lys，Mrp-Phe-Lys，D-Mrp-Phe-
Lys，Trp-Lys，
D-Trp-Lys，Mrp-Lys，D-Mrp-Lys，Ala-Trp-D-Phe-Lys，Ala-
Mrp-D-Phe-Lys，
Ala-D-Mrp-D-Phe-Lys，D-Lys-Trp-D-Phe-Lys，D-Lys-Mrp-D-
Phe-Lys，
D-Lys-D-Mrp-D-Phe-Lys，
或式VI三环化合物
其中的R5为H或SO2Me，并且*处的构型为(R)，(S)或其混合物；
且
E为Lys-NH2或-NH2，条件是C为前面定义的三环化合物VI时，E为Lys-NH2。
根据本发明，现已发现，GH释放化合物及不释放GH的化合物均对肿瘤的治疗有作用。根据本发明，优选的可治疗肿瘤包括肺肿瘤、乳腺肿瘤、甲状腺肿瘤或胰腺肿瘤。
特别优选的具式I的GH释放化合物包括以下化合物：
His-D-Trp-Ala-Trp-D-Phe-Lys-NH2，
His-D-Trp-Ala-Mrp-D-Phe-Lys-NH2，
D-Thr-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
Thr-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
IMA-D-Mrp-D-Trp-Phe-Lys-NH2，
IMA-D-Mrp-D-Nal-Phe-Lys-NH2，
GAB-D-Mrp-D-Mrp-D-Mrp-Lys-NH2，
D-Ala-D-Nal-Ala-Trp-D-Phe-Lys-NH2，
INIP-D-Nal-D-Nal-Phe-Lys-NH2，
INIP-D-Nal-D-Trp-Phe-Lys-NH2，
IMA-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
INIP-D-Mrp-D-Trp-Phe-Lys-NH2，
INIP-D-Mrp-D-Nal-Phe-Lys-NH2，
GAB-D-Mrp-D-Trp-Phe-Lys-NH2，
TXM-D-Mrp-D-Trp-Phe-Lys-NH2，
GAB-D-Mrp-Mrp-Phe-Lys-NH2，
Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
His-D-Mrp-Ala-Trp-D-Phe-Lys-Thr-NH2，
His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
D-Thr-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
GAB-D-Mrp-D-Nal-Phe-Lys-NH2，
GAB-D-Mrp-D-Mrp-Mrp-Lys-NH2，
Cys-Tyr-GAB-D-Mrp-D-Mrp-Mrp-Lys-NH2，
Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，和
D-Ala-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
优选的具通式I的不释效GH的化合物包括：
His-D-Trp-D-Lys-Trp-D-Phe-Lys-NH2，
His-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
His-Ala-D-Trp-Lys-Mrp-D-Phe-Lys-NH2，
His-D-Mrp-D-Lys-Mrp-D-Phe-Lys-NH2，
His-Ala-D-Trp-Ala-Mrp-D-Phe-Lys-NH2，和
His-D-Trp-Ala-Mrp-D-Phe-Lys-NH2。
优选的具通式II的化合物包括：
[S，S-Spiro(Pro-Leu)]-D-Mrp-D-Trp-Phe-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-Mrp-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
Tyr-[S，S-Spiro(Pro-Leu)]-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
[S，S-Spiro(Pro-Ile)]-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-D-HNH-(SO2CH3)-Phe-Lys-NH2，
HAIC-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，和
ATAB-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
其中的S，S-螺(Pro-Leu)和S，S-螺(Pro-Ile)相应地为4-甲基-2S[6’-氧-(5’-S)1’，7’-二氮杂螺[4，4]壬烷-7’-基-]戊酸酯(盐)和3-甲基-2S[6’-氧-(5’-S)1’，7’-二氮杂螺[4，4]壬烷-7’-基-]戊酸酯(盐)。
这些单位具有下式：
其中的R1为H且R2为Leu或Ile的侧链(参见P.Ward等人，J.Med.Chem.，33，1848(1990)。同样，对具有下式的相应的四氢降哈尔满-3-羧酸进行常规的氢化反应，可以得到三环化合物HNH
根据式III，IV，V和VI，这些单位构成仿肽单位，它们的优势在于它们锁于β-构型，从而可以模仿天然氨基酸。
如有所需，还可以使用这些化合物制药上可接受的盐类。这些盐类包括有机或无机加成盐，例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、酒石酸盐、葡糖酸盐、苯甲酸盐、苹果酸盐、富马酸盐、硬脂酸盐或双羟萘酸盐。
根据肽化学中常用的方法可以方便地合成所有的化合物，例如通过固相肽合成方法(参见E.Atherton和R.C.Sheppard在1989年由牛津大学出版社IRL出版的“固相肽合成”中的描述)，或通过溶液相合成方法(参见J.Jones在“肽类的化学合成”，Clarendon出版社，牛津1994中的描述)，或通过本领域内已知的固相-和液相方法的组合。
固相合成从化合物的C末端开始。将需要的保护α-氨基酸连接到氯代甲基化的树脂、羟甲基化树脂、二苯甲基胺树脂(BHA)或对-甲基-二苯甲基树脂(p-Me-BHA)上，可以制备得到合适的起始物质。例如，市售的氯代甲基化的树脂来自BioRad Laboratories，Richmond，California的Biobeads SX1。羟甲基化树脂的制备可以按照Bodansky等人在Chem.Ind.(London)，38，15997(1966)中所述的方法进行。BHA树脂的制备方法可以参见Pietta和Marshall，在Chem.Comm.，650(1970)中的描述，并可以在Peninsula Laboratories Inc.，Belmont，California购得。
在起始连接之后，通过不同的酸试剂除去α-氨基酸的保护基团，例如室温下溶于有机溶剂中的三氟乙酸(TFA)或盐酸(HCl)。除去α-氨基酸的保护基团之后，可以按照需要的顺序一步一步地使剩余的保护天然氨基酸或相应于通式HI、IV、V和VI单位的羧酸(其本身即构成氨基酸)进行偶联。通常使用约3倍过量的合适羧基活化基团(例如溶解于二氯甲烷(CH2Cl2)、二甲基甲酰胺(DMF)或其混合物中的二环己基碳化二亚胺(DCC)或二异丙基碳化二亚胺(DIC))使每一个保护氨基酸进行反应。在完成所需的氨基酸序列之后，通过用氟化氢(HF)等试剂进行处理，使需要的化合物从支持树脂上断裂下来，上述试剂不仅使化合物从树脂上断裂下来，而且使外侧链的保护基团断裂下来。当采用氯代甲基化的树脂时，采用HF的处理导致了具有终端酸基团化合物的形成，并且该化合物以游离形式存在。当采用BHA或p-Me-BHA树脂时，采用HF的处理直接导致了具有终端酰胺基团化合物的形成，并且该化合物以游离形式存在。
可用来治疗哺乳动物(包括人类)肿瘤的药物包括本发明化合物及其制药上可接受的盐类，或本发明化合物及其制药上可接受盐类任意地与载体、赋形剂、媒介物、稀释剂、基质或缓释包衣相混合物的组合物。这些载体、赋形剂、媒介物、稀释剂的实例可在Remington’sPharmaceutical Sciences，18th，A.R.Gennaro，Ed.，Mack PublishingCompany，Easton，PA 1990中找到。
本领域技术人员可将本发明中的任意化合物配成适合于经过非肠道、颊、直肠、阴道、皮透、肺或口服等途径给药的药物。
根据需要的释放速率，可以选择含有化合物药物的配方类型，例如，如果需要化合物迅速释放，可以采取鼻腔或静脉途径。
可以治疗有效剂量给予哺乳动物(包括人类)这些药物，本领域技术人员可以很容易地决定所述的治疗有效剂量，并需要根据物种、年龄、性别、治疗患者或对象的体重以及给药途径对该剂量进行适当的变化。例如对于人类而言，当采取静脉给药时，优选的剂量下降至约1-25μg总化合物/Kg体重。当采取口服给药时，通常需要较高的剂量。例如在人类进行口服给药时，典型的剂量水平约为30-1000μg总化合物/Kg体重。根据上述公开，可以根据经验决定药物的准确剂量。
实施例
下列实施例将说明用于治疗本发明肿瘤的最优选化合物的效力。
1.方法和材料
a)化学品
海噻瑞林(His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2)，Ala-海噻瑞林(Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2)，Tyr-Ala-海噻瑞林(Tyr-Ala-His-D-Mrp-Ala-Trp-D-Phe-Lys-NH2)，MK0677(N-[1(R)([1，2-二氢-1-甲磺酰基螺-(3H-吲哚，3，4’-哌啶)-1’基]-2-(苯基甲氧基)乙基]-2-氨基-甲基丙酰胺-甲磺酸酯(盐))，EP80317(HAIC-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2)和D-(Lys)3-GHRP6(His-D-Trp-D-Lys-Trp-D-Phe-Lys-NH2)由Europeptides(Argenteuil，法国)提供。人类GHRH(GHRH 1-44)和生长激素释放抑制因子(生长激素释放抑制因子1-14)可从Bachem(Bubendorf，Switzerland)购买。人类重组表皮生长因子(EGF)以及所有的组织培养试剂可从SigmaChemical Co.(St.Louis，MO，USA)购买。3H-胸腺嘧啶可从Pharmacia-Amersham Italia(Milan，Italy)购买。
b)人类组织
从Turin大学生物医学科学和人类肿瘤学系(病理学分部)采集外科肿瘤标本。将邻近用于医院病理学诊断的肿瘤切片立即冷冻在-80℃下，并储存2-6个月，直至进一步加工用于结合研究。采用13个侵入乳腺癌样品(10个为导管的，3个为小叶的)，14个非内分泌肺癌样品(5个鳞状细胞和9个腺癌细胞)，11个内分泌肺肿瘤样品，9个内分泌胰腺肿瘤样品以及12个甲状腺肿瘤样品(7个卵泡起源的，5个髓起源的)。同时对每一个肿瘤样品相应器官非肿瘤正常组织进行平行分析。
c)肿瘤细胞系
从ATCC(Rockville，MD，USA)购买人类肺肿瘤细胞样品(CaLu1)、T47D和MDA-MB231以及人类雌激素依赖和不依赖乳腺癌细胞系。在37℃并5％CO2和95％的湿度下于25cm3烧瓶中供济有10％FCS的RPMI中对细胞进行常规培养。当达到亚融合状态时，用胰蛋白酶/EDTA从烧瓶中分离出细胞。
d)GHRP受体分析
按照G.Muccioli等人在Journal of Endocrinology，157，99-106，1998中所述的方法，采用125I-Tyr-Ala-海噻瑞林作为配体，可以测定肿瘤膜上的GHRP受体。计算在缺乏和有过量未标记Tyr-Ala-海噻瑞林存在下特异性结合的差异，并用加入的放射活性的百分比来表示。用GraphPADPrism 2程序(GraphPAD Software，San Diego，CA，USA)对饱和及竞争性结合研究进行分析。
e)细胞繁殖研究
按照G.Muccioli等人在Journal of Endocrinology，153，365-371，1997中所述的3H-胸腺嘧啶混入方法对DNA合成进行评价。在缺乏和有不同浓度(10-8-10-6mol/l)海噻瑞林、Ala-海噻瑞林、Tyr-Ala-海噻瑞林、MK0677、D-(Lys)3-GHRP6或EP80317存在下，用单独培养基(基线)或带有EGF(1ng/ml)的培养基对饥饿细胞进行培养。培养20小时后，加入3H-胸腺嘧啶，继续培养4小时。终止反应，将细胞收集于玻璃纤维滤纸条上。用闪烁计数器测定3H-胸腺嘧啶的混入。
按照P.Cassoni等人在Virchows Archiv，425，467-472，1994中所描述的方法进行细胞生长研究。在24多孔平皿中种植细胞，密度为5,000-10,000细胞/ml，共3份平行样品。种植24小时后，改变培养基。在需要处加入海噻瑞林或Ala-海噻瑞林，浓度为10-8-10-6mol/l。每48小时改变培养基。采用血细胞计，由两个独立的调查者以双盲分析的方式，在处理48、72、96小时对细胞进行计数。
f)统计分析
除非另有说明，数据以平均值或平均值±S.E.M.表示。采用Mann-Whitnry检验或单道ANOVA来决定统计显著性。所有的实验至少做3份平行样。
2.结果
a)在不同人类肿瘤中GHRP及其拮抗剂受体的鉴别
肺和乳腺非内分泌肿瘤以及胰腺和甲状腺(小叶型)内分泌肿瘤显示出中等程度的特异性结合值，从统计学角度而言，高于在相应的非肿瘤正常组织中得到的结果。相反，在正常组织和肺或甲状腺(髓型)内分泌肿瘤之间在特异性结合值方面却没有差异。
b)GHRP及其拮抗剂受体的生化特征
为了测定125I-Tyr-Ala-海噻瑞林与肿瘤膜的结合是否显示配体-受体相互作用的典型性质，在肺起源的非内分泌肿瘤(其显示出最高的特异性结合值)中对放射示踪物的结合进行了更加详细的调查。此项研究揭示了可饱和的特异性结合的证据，并且Scatchard分析显示出存在单类的高亲和力部位。
通过测定不同化合物与放射配体竞争肿瘤结合部位的能力，可以建立125I-Tyr-Ala-海噻瑞林结合的特异性。放射示踪物的结合以剂量依赖方式被海噻瑞林、Ala-海噻瑞林、Tyr-Ala-海噻瑞林以及GHRP拮抗剂所取代，所述的拮抗剂例如有D-(Lys)3-GHRP6和EP80317(一种海噻瑞林的(氨基-氮杂-吲哚)D-(Lys)3衍生物，其在新生大鼠中不释放GH)。在MK0677(一种与垂体GHRP受体结合的非肽基GHRP模仿物)存在下，观察到不可忽略的取代。相反，在GHRP或生长激素释放抑制因子存在下，没有观察到竞争。
c)GHRP及其拮抗剂对3H-胸腺嘧啶混入的作用
浓度为10-6mol/l的海噻瑞林可以抑制人类肺肿瘤细胞中基本的和EGF-刺激的3H-胸腺嘧啶混入。当在有10-6mol/l的Ala-海噻瑞林、Tyr-Ala-海噻瑞林或GHRP拮抗剂所取代(例如D-(Lys)3-GHRP6和EP80317)存在下对细胞进行培养时，也观察到这种抗增殖作用。相反，在MK0677存在下，仅观察到轻微的抑制。采用增加浓度的海噻瑞林、Ala-海噻瑞林、Tyr-Ala-海噻瑞林、D-(Lys)3-GHRP6和EP80317的实验揭示这些化合物抑制了EGF对人类肺肿瘤细胞的增殖作用，所述的肺肿瘤细胞以剂量-依赖方式被抑制。EP80317的EC50值为5.6×10-8mol/l，Tyr-Ala-海噻瑞林的EC50值为6.5×10-8mol/l，海噻瑞林的EC50值为8×10-8mol/l，D-(Lys)3-GHRP6的EC50值为9×10-8mol/l，Ala-海噻瑞林的EC50值为1×10-7mol/l。
d)GHRP对细胞生长的作用
在人类肺肿瘤细胞中，与具有显著作用的对照相比(-47％)，仅在96小时后浓度为10-8mol/l的海噻瑞林可以引起细胞数量的下降。这种作用在10-7mol和10-6mol时会进一步增加，并可以在任意的实验时间点被观察到。
在人类乳腺癌T47D细胞中，与具有显著作用的对照相比(-54％)，仅在96小时后浓度为10-8mol/l的海噻瑞林可以引起细胞数量的下降。这种作用在10-7mol和10-6mol时会进一步增加，并可以在任意的实验时间点被观察到。Ala-海噻瑞林对这些肿瘤细胞也显示出相似的抗增殖作用。
在人类乳腺癌MDA-MB231细胞中，与具有显著作用的对照相比(-33％)，仅在72小时后浓度为10-8mol/l的海噻瑞林可以引起细胞数量的下降。这种作用在10-7mol和10-6mol时会进一步增加，并可以在任意的实验时间点被观察到。Ala-海噻瑞林对这些肿瘤细胞也显示出相似的抗增殖作用。
这些实验结果证明，合成的生长激素释放肽及其拮抗剂可以在体外抑制人类肿瘤细胞的生长。这种抗增殖作用是由特异性的受体介导的。
Claims (3)
1.化合物，其为：
His-D-Trp-D-Lys-Trp-D-Phe-Lys-NH2，
His-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
His-Ala-D-Trp-Lys-Mrp-D-Phe-Lys-NH2，
His-D-Mrp-D-Lys-Mrp-D-Phe-Lys-NH2，
His-Ala-D-Trp-Ala-Mrp-D-Phe-Lys-NH2，或
His-D-Trp-Ala-Mrp-D-Phe-Lys-NH2.
2.化合物，其为：
[S，S-Spiro(Pro-Leu)]-D-Mrp-D-Trp-Phe-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-Mrp-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-Ala-Trp-D-Phe-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
Tyr-[S，S-Spiro(Pro-Leu)]-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
[S，S-Spiro(Pro-Ile)]-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，
[S，S-Spiro(Pro-Leu)]-D-Mrp-D-HNH-(SO2CH3)-Phe-Lys-NH2，
HAIC-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2，或
ATAB-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2.
3.根据权利要求2的化合物，其为：
HAIC-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2.
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| EP1312363A1 (en) * | 2001-09-28 | 2003-05-21 | Pfizer Products Inc. | Methods of treatment and kits comprising a growth hormone secretagogue |
| TWI331922B (en) * | 2002-08-09 | 2010-10-21 | Ipsen Pharma Sas | Growth hormone releasing peptides |
| WO2005027913A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and a growth hormone secretagogue |
| US20050164952A1 (en) * | 2004-01-23 | 2005-07-28 | Vital Pharmaceuticals, Inc. | Delivery system for growth hormone releasing peptides |
| EP2021015A2 (en) * | 2006-04-28 | 2009-02-11 | The Administrators Of The Tulane Educational Fund | Ghrelin/growth hormone releasing peptide/growth hormone secretatogue receptor antagonists and uses thereof |
| KR101197541B1 (ko) | 2006-09-27 | 2013-01-02 | 입센 파마 에스.에이.에스 | Ｎ-말단이 치환된 그렐린 유사체 |
| EP2134341B1 (en) * | 2007-02-13 | 2015-06-17 | Helsinn Healthcare S.A. | Method of treating cell proliferative disorders using growth hormone secretagogues |
| US8841257B2 (en) * | 2009-04-10 | 2014-09-23 | Board Of Regents, The University Of Texas System | Inhibitors of STAT3 and uses thereof |
| US9724381B2 (en) | 2009-05-12 | 2017-08-08 | The Administrators Of The Tulane Educational Fund | Methods of inhibiting the ghrelin/growth hormone secretatogue receptor pathway and uses thereof |
| IT1399610B1 (it) * | 2010-01-28 | 2013-04-26 | Univ Milano Bicocca | Uso di agonisti e antagonisti dei recettori per i growth hormone secretagogues per la prevenzione e il trattamento di convulsioni ed epilessia |
| EP3920961A4 (en) | 2019-02-08 | 2022-12-14 | United States Government as represented by the Department of Veterans Affairs | GROWTH HORMONE RELEASING HORMONE ANTAGONISTS AND THEIR USES |
| CN118021978A (zh) * | 2019-07-18 | 2024-05-14 | 迈阿密大学 | 用于治疗结节病的方法的ghrh拮抗剂 |
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| CA2053250A1 (en) * | 1989-04-26 | 1990-10-27 | David H. Coy | Linear somatostatin analogs |
| IT1240643B (it) * | 1990-05-11 | 1993-12-17 | Mediolanum Farmaceutici Spa | Peptidi biologicamente attivi contenenti in catena 2-alchiltriptofano |
| US5385682A (en) * | 1990-05-15 | 1995-01-31 | Exxon Research & Engineering Co. | Grease composition |
| SK15096A3 (en) * | 1993-08-09 | 1996-07-03 | Biomeasure Inc | Therapeutic peptide derivatives and a method of their application |
| US5550212A (en) * | 1993-12-17 | 1996-08-27 | The Administrators Of The Tulane Educational Fund | Analogues of hGH-RH(1-29)NH2 having antagonistic activity |
| US5807985A (en) * | 1996-06-11 | 1998-09-15 | Deghenghi; Romano | Oligopeptide compounds containing D-2-alkyltryptophan capable of promoting the release of growth hormone |
| US6063796A (en) * | 1997-04-04 | 2000-05-16 | Merck & Co., Inc. | Somatostatin agonists |
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