CN1367792A - 促生长素抑制素激动剂 - Google Patents
促生长素抑制素激动剂 Download PDFInfo
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- CN1367792A CN1367792A CN00811189A CN00811189A CN1367792A CN 1367792 A CN1367792 A CN 1367792A CN 00811189 A CN00811189 A CN 00811189A CN 00811189 A CN00811189 A CN 00811189A CN 1367792 A CN1367792 A CN 1367792A
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Abstract
本发明涉及到化学式(I)的环肽:X-A1-环(D-Cys-A3-A4-Lys-A6-A7)-A8-Y,或其药学上可接受的盐,其中X是H,式(a)或式(b);A1和A3每个独自是选自以下组的氨基酸的D-或L-异构体:Phe、Tyr、Tyr(I)、Trp、3-Pal、4-Pal、Cpa和Nal;A4是L-Trp、D-Trp、L-β-甲基-Trp或D-β-甲基-Trp;A6是-NH-(CHR1)n-CO-,这里n是2、3或4;A7是L-或D-Cys;A8是选自以下组的氨基酸的D-或L-异构体:Phe、Tyr、Tyr(1)、Trp、Nal、Cpa、Val、Leu、lle、Ser和Thr;Y是NR2R3,这里R2和R3每个独自是H或(C1-C5)烷基;R1选自H、(C1-C4)烷基和-CH2-芳基;其中所述的芳基是选择性取代的部分,它选自苯基、1-萘基和2-萘基,其中所述的选择性取代部分是选择性地以一个或多个取代基取代,每个取代基独自选自以下基团:(C1-6)烷基、(C2-6)烯基、(C2-6)炔基、芳基、芳基(C1-6)烷基、(C1-6)烷氧基、-N(R4R5)、-COOH、-CON(R4R5)、卤素、-OH、-CN和-NO2;R4和R5对于各自的情形,每个独自是H或(C1-3)烷基;这里A2的Cys与A7的Cys通过由每个Cys的硫羟基形成的二硫键键合。含有所述肽的药物组合物和其作为促生长素抑制素受体亚型激动剂的用途。本发明的肽选择性地与促生长素抑制素亚型5-型受体结合,并且引起来自该肽结合的促生长素抑制素亚型受体的激动剂的作用。
Description
发明背景
本发明涉及在下文显示和定义的具有促生长素抑制素激动剂活性的环肽,如式(I)定义,或其药学上可接受的盐,含有所述肽的药物组合物以及其作为促生长素抑制素受体亚型激动剂的用途。本发明的肽选择性地与促生长素抑制素亚型5型受体结合,并且引起来自该肽结合的促生长素抑制素亚型受体的激动剂作用。
促生长素抑制素(SRIF)是一种含有3位和14位之间的二硫桥的环十四肽激素(Heiman,等人,Neuroendocrinology,45:429-436(1987))。并且具有下列性质:抑制生长激素(GH)和促甲状腺激素的释放(TSH),抑制糊精、胰岛素和胰高血糖素的释放,减小胃液分泌和神经递质的释放。促生长素抑制素通过氨肽酶和羧肽酶的代谢导致短持续时间的作用。由于天然促生长素抑制素的短半衰期,已研发了各种促生长素抑制素类似物,例如,用于治疗肢端肥大症。Raynor,等人,Molecular Pharmacol.43:838(1993)。
已鉴定并表征了5种不同的促生长素抑制素受体。Hoyer,等人,Naunyn-Schmiedeberg’s Arch.Pharmacol.,350:441(1994)。促生长素抑制素与五种不同的受体(SSTR)亚型结合,对于每种亚型具有较高且相等的亲和性。已经将与不同类型的促生长素抑制素亚型的结合与下列症状和/或疾病联系起来。(″SSTR-2″)(Raynor,等人,Molecular Pharmacol.43:838(1993);Lloyd,等人,Am.J.Physiol.268:G102(1995)),而胰岛素的抑制已归因于促生长素抑制素5-型受体(″SSTR-5″)(Coy,等人197:366-371(1993))。2型和5型的激活已与生长激素抑制和更具体的GH分泌腺瘤(肢端肥大症)和TSH分泌腺瘤有关。2型而不是5型的激活与治疗催乳激素分泌腺瘤有关。其它与促生长素抑制素亚型的激活有关的适应症是抑制胰岛素和/或胰高血糖素,更具体地是糖尿病、血管病、增生的视网膜病、凌晨发作(dawn)现象和肾病;抑制胃酸分泌,更具体地是消化性溃疡、肠皮瘘和胰管皮瘘、过敏性肠综合征、胃切除术后综合征、水泻综合征、AIDS相关的腹泻、化学疗法引起的腹泻、急性或慢性胰腺炎和胃肠激素分泌瘤;癌症的治疗,例如肝细胞瘤;抑制血管生成,炎性疾病的治疗,例如关节炎;视网膜病;慢性同种异体移植物的排斥;血管成形术;预防移植血管(graft vessel)和胃肠出血。优选具有一种对决定所需要的生物学反应的专一促生长素抑制素受体亚型有选择性的类似物,从而,减少可能引起不希望的副反应的与其它受体亚型之间的相互作用。
式(I)的肽是一种亚属,它包括在待审的、1997年5月13日提交的美国申请No.08/855,204描述和要求保护的化合物属中,该申请已部分转让给本发明的受让人。在美国申请No.08/855,204中未具体描述本申请式(I)化合物。令人惊奇和意料之外地,本发明式(I)化合物具有促生长素抑制素激动剂活性。这是一种意料之外和令人惊奇的发现,由于最初发现美国申请No.08/855,204的化合物具有促生长素抑制素拮抗剂活性。
发明概述
一方面,本发明涉及式(1)的肽,
X-A1-环(D-Cys-A3-A4-Lys-A6-A7)-A8-Y,
(I)
或其药学上可接受的盐,
其中
A1和A3每个独自选自以下组的氨基酸的D-或L-异构体:Phe、Tyr、Tyr(I)、Trp、3-Pal、4-Pal、Cpa和Nal;
A4是L-Trp、D-Trp、L-β-甲基-Trp或D-β-甲基-Trp;
A6是-NH-(CHR1)n-CO-,这里n是2、3或4;
A7是L-或D-Cys;
A8选自以下组的氨基酸的D-或L-异构体:Phe、Tyr、Tyr(l)、Trp、Nal、Cpa、Val、Leu、Ile、Ser和Thr;
Y是NR2R3,这里R2和R3每个独自是H或(C1-C5)烷基;
R1选自H、(C1-C4)烷基和-CH2-芳基;其中所述的芳基是选择性取代的部分,它选自苯基、1-萘基和2-萘基,其中所述的选择性取代的部分是选择性地以一个或多个取代基取代,每个取代基独自选自以下基团:(C1-6)烷基、(C2-6)烯基、(C2-6)炔基、芳基、芳基(C1-6)烷基、(C1-6)烷氧基、-N(R4R5)、-COOH、-CON(R4R5)、卤素、-OH、-CN和-NO2;
R4和R5对于各自的情形,每个独自是H或(C1-3)烷基;
这里A2的Cys与A7的Cys通过由每个Cys的硫羟基形成的二硫键键合。
前述式(I)的肽中优选一类肽是:
其中
X是H;
A1是L-Phe、D-Phe、L-Cpa或D-Cpa;
A3是L-Tyr、L-Trp或L-3-Pal;
A4是D-Trp;
A6是β-Ala或γ氨基丁酸(Gaba);
A7是L-Cys;
A8是Thr、L-Trp、L-Leu或L-Nal;和
R2和R3每个是H;或其药学上可接受的盐。
刚述及的肽的优选肽是:
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-β-Ala-Cys)-Nal-NH2;
Phe-环(D-Cys-3-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Phe-环(D-Cys-Trp-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Trp-NH2;
D-Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
D-Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Leu-NH2;和
Phe-环-(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Thr-NH2;或其药学上可接受的盐。
刚述及的肽的优选肽是:
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2;和
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-β-Ala-Cys)-Nal-NH2;或其药学上可接受的盐。
另一方面,本发明提供一种用于在人或其它动物中引起促生长素抑制素激动剂反应的药物组合物,它包括有效量的式(I)的肽或其药学上可接受的盐,以及药学上可接受的载体。
又一方面,本发明提供一种在人或其它动物中引起对其需要的促生长素抑制素激动剂反应的方法,它包括给予人或其它的动物有效量的式(I)的肽或其药学上可接受的盐。
进一步的方面,本发明提供一种在人或其它动物中选择性地结合促生长素抑制素亚型5型受体的方法,它包括给予人或其它的动物有效量的式(I)的肽或其药学上可接受的盐。
在又进一步的方面,本发明提供一种对人或其它动物需要治疗的疾病或病症的方法,它包括给予人或其它的动物有效量的式(I)的肽或其药学上可接受的盐,其中所述的疾病或病症选自:库兴氏综合征、促性腺素瘤(gonadotropinoma)、甲状旁腺功能亢进、佩吉特氏疾病、VIP肿瘤、胰岛细胞增殖症、胰岛素分泌过多、促胃泌素瘤、卓林格-艾丽逊综合征、与AIDS和其它病症有关的分泌过多的腹泻、过敏性肠综合征、胰腺炎、克罗恩氏病、***性硬化症、甲状腺癌、牛皮癣、低血压、恐慌发作、硬皮病(sclerodoma)、小肠梗阻、胃食管回流、十二指肠胃回流、葛雷夫斯氏病、多囊卵巢疾病、上胃肠出血、假性胰腺囊肿、胰腺腹水(pancreatic ascites)、白血病、脑膜瘤、癌恶病质、肢端肥大症、再狭窄、肝细胞瘤、肺癌、黑素瘤、抑制快速生长的实体瘤、减轻体重、治疗胰岛素耐药性、综合征X、延长胰腺细胞存活、纤维样变性、高脂血症、高淀粉粒纤维素血症(hyperamylinemia)、高催乳素血症和催乳素血症(prolactinemia)。
在还进一步的方面,本发明提供一种抑制人或其它动物中所需的生长激素、胰岛素、胰高血糖素或胰腺外分泌物分泌的方法,它包括给予人或其它动物有效量的式(I)的肽或其药学上可接受的盐。
在更进一步的方面,本发明提供一种人或其它动物中含促生长素抑制素受体的细胞的体内造影方法,它包括给予人或其它动物式(I)的肽,条件是A1、A3或A8中的至少一个是Tyr(I),或其药学上可接受的盐。
另一方面,本发明提供一种含促生长素抑制素受体的细胞体外造影方法,它包括给予人或其它动物式(I)的肽,条件是A1、A3或A8中的至少一个是Tyr(I),或其药学上可接受的盐。这种本发明的肽或以用于体内检测具有促生长素抑制素受体的细胞(例如,癌细胞),或者体外作为促生长素抑制素受体结合试验中的放射性配位体。
本领域接受的3个字母的缩写用于指本发明肽中的氨基酸。本文所列的式中,未显示残基A2侧链上的硫羟基(即,D-Cys)和残基A7侧链上的硫羟基(即,L-Cys或D-Cys)之间的二硫键。下列氨基酸缩写代表其之后表示的名称:Cpa=对氯苯基丙氨酸;Nal=β-(2-萘基))丙氨酸;3-Pal=β-(3-吡啶基)丙氨酸;4-Pal=β-(4-吡啶基))丙氨酸;和Gaba=4-氨基丁酸。″-NH-(CH2)n-CO-,这里n是2、3或4″的定义包括这样的氨基酸,如β-Ala和Gaba。
除非另有说明,氨基酸的3个字母缩写指L-异构体。
术语烷基是指包括指定直链或支链构型长度的烷基基团。这类烷基基团的实例是甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、异戊基等等。当定义包括术语Co-烷基时,它表示单一共价键。
术语烯基是指包括具有一个或多个双键和在直链或支链构型上指定碳原子数目的烃基。这类烯基的典型实例是乙烯基、丙烯基、异丙烯基、丁烯基、仲丁烯基、叔丁烯基、戊烯基、异戊烯基、己烯基、异己烯基等等。
术语炔基是指包括那些炔基基团,即,具有一个或多个三键,在直链或支链构型上具有指定碳原子数目的烃基。这类炔基的典型实例是乙炔基、丙炔基、丁炔基、戊炔基、异戊炔基、己炔基、异己炔基等等。
术语烷氧基是指包括在直链或支链构型上具有指定碳原子数目的那些烷氧基。这类烷氧基的典型实例是甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、异戊氧基、己氧基、异己氧基等等。
术语芳基是指包括本领域已知的芳环,它可以是单环或双环,例如苯基和萘基。
术语卤素是指包括氯、溴、碘和氟。详细说明
基于本文的描述,本领域的熟练技术人员在其最完全的程度内利用本发明。因此,下列具体的实施方案仅构成作为本发明的例证,并不意味构成作为限制本发明的全部范围。
本发明的肽可以并在Rink Amide MBHA树脂(4-(2’,4’-二甲氧基苯基-9-芴基甲氧羰基(Fmoc)-氨基甲基)苯氧基乙酰氨基-正亮氨酰基-MBHA树脂)上,采用FMOC化学的标准固相方案合成,并以TFA/苯酚/H2O/三异丙基硅烷(83ml/5g/10ml/2ml)混合物从树脂上分开。采用EKATHIOXTM树脂(EKAGEN公司,San Carlos,CA)在CH3CN/H2O(5ml/5ml)中环化该肽,并且在C18二氧化硅(Rainin仪器公司,Woburn,MA now VarianAnalytical,Walnut Creek,CA)上,采用乙腈/0.1%三氟醋酸缓冲剂纯化。通过分析HPLC评估均一性,且对于每种肽测定均一性>95%。通过质谱表征肽。
本发明式(I)的碘化Tyr(Tyr(I))肽的合成(例如,氯胺-T法)已经良好地记载在文献中,并在本领域普通熟练技术人员的能力之内。参见,例如,Czernick,等人,J.Biol.Chem.258:5525(1993)和欧洲专利No.389,180 B1。
以下是实施例1和2的合成的详细说明。式(I)化合物中的其它肽可通过进行适当的、肽合成领域普通技术人员公知的修改来制备。
实施例1
步骤1=Fmoc-Cpa-S-三苯甲基-D-Cys-Pal-N-in-t-Boc-D-Trp-N-ε-t-Boc-Lys-β-Ala-S-三苯甲基-Cys-Nal-4-(2’,4’-二甲氧基苯基氨基甲基)苯氧基-乙酰氨基-正亮氨酰基-4-甲基二苯甲基胺树脂的制备。
Rink酰胺MBHA树脂(Novabiochem,Inc.,San Diego,CA)0.5g(0.265mmole),置于24-RV肽合成器的反应器内,它装配有连接的震动器(来自Burrell Wrist-Action Laboratory Shaker)、溶剂分布器和真空泵。设置这种肽合成器的程序,以进行下列的反应循环:
a. 二甲基甲酰胺;
b. 25%哌啶的二甲基甲酰胺溶液(手工加入)(2次,每次15分钟,中间以DMF洗涤1次);
c. DMF洗涤(3×10mL,每次1分钟);
在二甲基甲酰胺中,这种树脂与FMOC-Nal(1.06mmol)、2-(1H-苯并***-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(HBUT)1.007mmole)以及二异丙基乙基胺(2.12mmole)搅拌大约1.5小时,所得的氨基酸树脂接着经步骤(a)至(c)在上述的洗涤/解封程序中循环。
下列氨基酸通过同样的步骤接着偶合至该Nal-树脂上:Fmoc-S-三苯甲基-Cys、Fmoc-β-Ala、N-ε-t-Boc-Lys、Fmoc-(N-in-t-Boc)-D-Trp、Fmoc-Pal、Fmoc-S-三苯甲基-D-Cys和Fmoc-p-Cl-Phe。
以DMF洗涤(3×10mL,每次大约1分钟)和真空干燥之后,完成的肽树脂重0.749g。
步骤2:H-Cpa-环(D-Cys-Pal-D-Trp-Lys-β-Ala-Cys)-Nal-NH2的制备
实施例1的步骤1获得的肽树脂(0.36g,0.087mmole)于室温下混入以TFA(8.8mL)、苯酚(0.5g)、H2O(0.5mL)和三异丙基硅烷(0.2mL)新制备的溶液,并搅拌大约2.5小时。减压蒸发过量的TFA以产生油状残余物。然后向这种油状残余物中加入***,沉淀游离的线型肽,过滤并以干燥***洗涤。粗产物肽接着溶于10mL的CH3CN/H2O(5mL/5mL),然后加入200mgEKATHIOXTM树脂。该混合物搅拌过夜并过滤。滤液蒸发至较小体积然后上微吸附十八烷基硅烷二氧化硅柱(22-250mm)(5μm)。以线性梯度(20%至40%,60分钟内)的乙腈水溶液洗脱(两种溶剂含有0.1%三氟醋酸),产生由分析高性能液相色谱法(’HPLC″)检测和汇集以给予最大纯度的馏分。溶液从水中冷冻干燥,产生26mg白色松散粉末产品。通过HPLC C18二氧化硅,采用如上描述的同一洗脱剂和线性梯度(30%至70%,经15分钟)(保留时间6.313分钟),发现产物是均一的。注入质谱法确认这种环八肽成分,MW 1133.8。
实施例2
步骤1:Fmoc-Cpa-S-三三苯甲基-D-Cys-Pal-in-t-Boc-D-Trp-N-ε-t-Boc-Lys-Gaba-S-三苯甲基-Cys-Nal-4-(2’,4’-二甲氧基苯基氨基甲基)苯氧基乙酰氨基-正亮氨酰基-4-甲基二苯甲基胺树脂的制备
Rink酰胺MBHA树脂(Novabiochem,Inc.San Diego,CA)0.2g(0.106mmole)置入24-RV肽合成器的反应器#3,(RV-3)。设置这种肽合成器的程序,以进行下列的反应循环:
a. 二甲基甲酰胺;
b. 25%哌啶的二甲基甲酰胺溶液(手工加入)(2次,每次15分钟,中间以DMF洗涤1次);
c. DMF洗涤(3×10mL,每次1分钟);
在二甲基甲酰胺中,这种树脂与FMOC-Nal(0.424mmol)、2-(1H-苯并***-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(HBUT)(0.403mmole),以及二异丙基乙基胺(0.848mmole)搅拌大约1.5小时,所得的氨基酸树脂接着经步骤(a)至(c)在上述的洗涤程序中循环。
下列氨基酸通过同样的步骤接着偶合至该肽树脂上:Fmoc-S-三苯甲基-Cys、Fmoc-Gaba、N-ε-t-Boc-Lys、Fmoc-(N-in-t-Boc)-D-Trp、Fmoc-Pal、Fmoc-S-三苯甲基-D-Cys和Fmoc-Cpa。以DMF洗涤(3×10mL,每次大约1分钟)和真空干燥之后,完成的肽树脂重0.31g。
步骤2:H-Cpa-环(D-Cys-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2的制备
实施例2的步骤1获得的肽树脂于室温下混入以TFA(8.3mL)、苯酚(0.5g)、H2O(1mL)和三异丙基硅烷(0.2mL)新制备的溶液,并搅拌大约2.5小时。减压蒸发过量的TFA以产生油状残余物。然后向这种油状残余物中加入***,沉淀游离的线型肽,过滤并以干燥***洗涤。粗产物肽接着溶于10mL的CH3CN/H2O,然后加入200mg EKATHIOXTM树脂。该混合物搅拌过夜并过滤。滤液蒸发至较小体积然后上微吸附十八烷基硅烷二氧化硅柱(22-250mm)(5μm)。以线性梯度(20%至100%,经60分钟)的乙腈水溶液洗脱(两种溶剂含有0.1%三氟醋酸)。由分析高性能液相色谱法(’HPLC″)检测和汇集馏分,以给予最大纯度。溶液从水中冷冻干燥,产生13mg白色松散粉末产品。通过HPLC C18二氧化硅,采用如上描述的相同洗脱剂(20%至80%,经15分钟内)(保留时间9.915分钟),发现产物是均一的。注入质谱法确认这种环八肽成分,MW 1147.83。
本发明的肽可以以药学上可接受的盐的形式提供。这类盐的例子包括(但不限于此)与有机酸(例如,醋酸、乳酸、马来酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、甲磺酸、甲苯磺酸或扑酸(pamoic acid))、无机酸(例如,盐酸、硫酸或磷酸)和聚合酸(例如,丹宁酸、羧甲基纤维素、聚乳酸、聚乙二醇酸或聚乳酸-乙二醇酸的共聚物)形成的那些盐。制备本发明的肽盐的典型方法本领域是公知的,并且可以通过盐交换标准方法完成。因此,本发明肽的TFA盐(这种TFA盐通过采用制备性HPLC、以含TFA缓冲溶液洗脱的肽的纯化产生)可以转化成另一种盐,例如通过溶解该肽在少量0.25N醋酸水溶液中转化的醋酸盐。所得的溶液上半-预备HPLC柱(Zorbax,300 SB,C-8)。该柱以(1)0.1N醋酸铵水溶液洗脱0.5小时,(2)0.25N醋酸水溶液洗脱0.5小时,以及(3)线性梯度(20%至100%溶液B,经30分钟)以4ml/分钟的流速(溶液A是0.25N醋酸水溶液;溶液B是0.25N醋酸的乙腈/水的溶液,80∶20)。收集含有该肽的馏分并冷冻至干。
本发明肽对于人促生长素抑制素亚型受体1至5(分别为sst1、sst2,、sst3、sst4和sst5)亲和性,通过测定抑制(125I-Tyr11)SRIF-14与CHO-K1转染细胞的结合来检测。
克隆人sst1受体基因作为基因组的片段。通过Bglll连接附加来修正含有100bp 5’-非翻译区、1.17Kb全部编码区和230bp 3’-非翻译区的1.5Kb Pstl-Xmnl片段。所得的DNA片段亚克隆至pCMV-81的BamHl位点,以产生哺乳动物表达质粒(Graeme Bell博士提供,芝加哥大学)。通过采用磷酸钙共-沉淀法(1)转染至CHO-K1细胞(ATCC)获得稳定表达sst1受体的克隆的细胞系。作为选择性标记包括质粒pRSV-neo(ATCC)。在含有环克隆克隆的0.5mg/ml G418的RPMI 1640培养基(Gibco)中选择克隆的细胞系,并扩散入培养物。
人sst2促生长素抑制素受体基因分离为1.7Kb BamHl-Hindlll基因组DNA片段并亚克隆入质粒载体pGEM3Z(Promega),由G.Bell博士友好地提供(芝加哥大学)。通过***这种1.7Kb BamHl-Hindll片段至质粒pCMV5相容的限制核酸内切酶位点,构建哺乳动物细胞表达载体。通过采用磷酸钙共-沉淀法(1)转染至CHO-K1细胞来获得克隆的细胞系。作为选择性标记包括质粒pRSV-neo。
人sst3在基因组片段被分离,完全的编码序列包含在2.4KbBamHllHindlll片段内。在EcoR1接头末端和添加修正之后,通过***2.0Kb Ncol-Hindlll片段至pCMV载体的EcoR1位点,构建哺乳动物表达质粒pCMV-h3。通过采用磷酸钙共-沉淀法转染至CHO-K1细胞(ATCC)获得稳定表达该sst3受体的克隆的细胞系。作为选择性标记包括质粒pRSV-neo(ATCC)。在含有环克隆克隆的0.5mg/ml G418的RPMI 1640培养基(Gibco)中选择克隆的细胞系,并扩散入培养物。
人sst4受体表达质粒,pCMV-HX由Graeme Bell博士提供(芝加哥大学)。该载体含有1.4Kb编码人sst4的Nhel-Nhei基因组片段,456bp 5’-非翻译区和200bp 3’-非翻译区,克隆入PCMV-HX的Xbal/EcoR1位点。通过采用磷酸钙共-沉淀法转染至CHO-K1细胞(ATCC)获得稳定表达sst4受体的克隆的细胞系。作为选择性标记包括质粒pRSV-neo(ATCC)。在含有环克隆克隆的0.5mg/ml G418的RPMI 1640培养基(Gibco)中选择克隆的细胞系,并扩散入培养物。
采用λ基因组的PCR克隆为模板,得到人sst5基因,并由Graeme Bell博士友好地提供(芝加哥大学)。所得的1.2Kb PCR片段含有21个5′-非翻译区的碱基对、完全编码区和55bp的3′-非翻译区。克隆***质粒pBSSK(+)的EcoR1位点。***物恢复为1.2Kb Hindlll-Xbal片段,以亚克隆入pCVM5哺乳动物表达载体。通过采用磷酸钙共-沉淀法转染至CHO-K1细胞(ATCC)获得稳定表达SST5受体的克隆的细胞系。作为选择性标记包括质粒pRSV-neo(ATCC)。在含有环克隆克隆的0.5mg/ml G418的RPMI 1640培养基(Gibco)中选择克隆的细胞系,并扩散入培养物。
稳定表达人sst受体之中一种的CHO-K1细胞在含有10%胎儿牛血清和0.4mg/ml遗传霉素的RPMI 1640中生长。以0.5mM EDTA收集细胞,并且在大约4℃,于500g离心大约5分钟。颗粒再悬浮入50mM Tris,pH7.4,并在大约4℃,于500g二次离心大约5分钟。该细胞通过超声处理溶解,并在大约4℃,于39000g离心大约10分钟。颗粒再悬浮于同一缓冲液中并在大约4℃于50000g离心大约10分钟,由颗粒制备的膜在-80℃贮藏。
(125I-Tyr11)SRIF-14结合的竞争抑制试验在双份聚丙烯96小孔板中进行。细胞膜(10μg蛋白/孔)与(125I-Tyr11)SRIF-14(0.05nM)一起,在大约37℃,于50mM HEPES(pH7.4)、0.2% BSA、5mM MgCl2、200KIU/ml抑肽酶、0.02mg/ml杆菌肽和0.02mg/ml苯甲基磺酰氟中培养大约60分钟。
采用Filtermate 196(Packard)细胞收获器,来自游离(125I-Tyr11)SRIF-14的结合通过经以0.1%聚乙烯亚胺(P.E.I.)预先浸渍的GF/C玻璃纤维滤板(Unifilter,Packard)的快速过滤来分离。以50mMHEPES在大约0-4℃洗涤滤器大约4秒,并且采用Packard Top Count试验放射性。
通过从总的结合中减去非特异结合(0.1μM SRIF-14存在下测量)得到特异结合。通过计算机辅助的非线性回归分析(MDL)来分析结合数据,并且确定抑制常数(Ki)值。
目前本发明化合物是激动剂还是拮抗剂的判定通过下列试验决定。
功能试验:抑制cAMP细胞内生成:
表达人促生长素抑制素(SRIF-14)亚型受体的CHO-K1细胞接种在24-孔组织培养多盘内含10% FCS和0.4mg/ml遗传霉素的RPMI 1640培养基中。试验前一天更换培养基。
105细胞/孔的细胞由0.5ml和含补充了0.5mM(1)3-异丁基-1-甲基黄嘌呤(IBMX)的0.2% BSA新鲜RPMI洗涤2次,并在大约37℃培养大约5分钟。
◆通过加入1mM毛喉素(FSK),在大约37℃,约15-30分钟,来刺激
环AMP的产生。
◆通过同时加入FSK(1μM)、SRIF-14(10-12M至10-6M)和试验化合物
(10-10M至10-5M)测量化合物的激动剂作用。
◆通过同时加入FSK(1μM)、SRIF-14(1至10nM)和试验化合物(10-10M
至10-5M)测量化合物的激动剂作用。
除去反应介质,并加入200ml 0.1N HCl。采用放射免疫测定法测量cAMP(Kit FlashPlate SMP001A,New England Nuclear)。
由于对于本领域熟练技术人员是公知的,促生长素抑制素已知和有效的用途是不同且多种多样的。从而,本发明肽的刺激促生长素抑制素受体的给药可具有正如促生长素抑制素本身同样的作用和用途。例如,抑制生长激素、胰岛素、胰高血糖素和胰腺外分泌物的分泌(美国专利No.4,853,371);治疗再狭窄(美国专利No.5,147,856);治疗肝细胞瘤(美国专利No.5,411,943);治疗肺癌(美国专利No.5,073,541);治疗黑瘤(1993年7月9日提交的美国申请No.08/089,410);抑制加速生长的实体瘤(美国专利No.5,504,069);减轻体重(1997年5月13日提交的美国申请No.08/854,941);治疗胰岛素耐药性和综合征X(1997年5月13日提交的美国申请No.08/854,943);延长胰腺细胞存活(美国专利No.5,688,418);治疗纤维变性(PCT申请No.PCT/US97/14154);治疗高脂血(1997年5月13日提交的美国申请No.08/855,311);治疗高淀粉粒纤维素血症(hyperamylinemia)(1995年5月12日提交的美国申请No.08/440,061);治疗高催乳素血症和催乳素血症(prolactinemia)(1997年5月7日提交的美国申请No.08/852,221);库兴氏综合征(参见Clark,R.V.等人,Clin.Res.38,p.943A,1990);促性腺素瘤(gonadotropinoma)(参见Ambrosi B.,等人,Acta Endocr.(Copenh.)122,569-576,1990);甲状旁腺功能亢进(参见Miller,D.,等人,Canad.Med.Ass.J.,Vol.145,pp.227-228,1991);佩吉特氏疾病(参见,Palmier,G.M.A.,等人,J.of Bone和Mineral Research,7,(Suppl.1),p.S240(Abs.591),1992);,VIP肿瘤(参见Koberstein,B.,等人,Z.Gastroenterology,28,295-301,1990和Christensen,C.,ActaChir.Scand.155,541-543,1989);胰岛细胞增殖症和胰岛素分泌过多(参见Laron,Z.,Israel J.Med.Sci.,26,No.1,1-2,1990,Wilson,D.C.,Irish J.Med.Sci.,158,No.1,31-32,1989和Micic,D.,等人,Digestion,16,Suppl.1.70.Abs.193,1990);促胃泌素瘤(参见Bauer,F.E.,等人,Europ.J.Pharmacol.,183,55 1990);卓林格-艾丽逊综合征(参见Mozell,E.,等人,Surg.Gynec.Obstet.,170,476-484,1990);与AIDS和其它病症有关的分泌过多的腹泻(归因于AIDS,参见Cello,J.P.,等人,Gastroenterology,98,No.5,Part 2,Suppl.,A163 1990;归因于升高的促胃泌素-释放肽,参见Alhindawi,R.,等人,Can.J.Surg.,33,139-142,1990;secondary to intestinal graft vs.host disease,参见Bianco J.A.,等人,Transplantation,49,1194-1195,1990;diarrhea associated with chemotherapy,参见Petrelli,N.,等人,Proc.Amer.Soc.Clin.Oncol.,Vol.10,P138,Abstr.No.417 1991);过敏性肠综合征(参见O’Donnell,L.J.D.,等人,Aliment.Pharmacol.Therap.,Vol.4.,177-181,1990);胰腺炎(参见Tulassay,Z.,等人,Gastroenterology,98,No.5,Part 2,Suppl.,A238,1990);克罗恩氏病(参见Fedorak,R.N.,等人,Can.J.Gastroenterology,3,No.2,53-57,1989);***性硬化症(参见Soudah,H.,等人,Gastroenterology,98,No.5,Part 2,Suppl.,A129,1990);甲状腺癌(参见Modigliani,E.,等人,Ann.,Endocr.(Paris),50,483-488,1989);牛皮癣(参见Camisa,C.,等人,Cleveland Clinic J.Med.,57,No.1,71-76,1990);低血压(参见Hoeldtke,R.D.,等人,Arch.Phys.Med.Rehabil.,69,895-898,1988和Kooner,J.S.,等人,Brit.J.Clin.Pharmacol.,28,735P-736P,1989);恐慌发作(参见Abelson,J.L,等人,Clin.Psychopharmacol.,10,128-132,1990);硬皮病(参见Soudah,H.,等人,Clin.Res.,Vol.39,p.303A,1991);小肠梗阻(参见Nott,D.M.,等人,Brit.J.Surg.,Vol.77,p.A691,1990);胃食管回流(参见Branch,M.S.,等人,Gastroenterology,Vol.100,No.5,Part 2 Suppl.,p.A425,1991);十二指肠胃回流(参见Hasler,W.,等人,Gastroenterology,Vol.100,No.5,Part 2,Suppl.,p.A448,1991);葛雷夫斯氏病(参见Chang,T.C.,等人,Brit.Med.J.,304,p.158,1992);多囊卵巢疾病(参见Prelevic,G.M.,等人,Metabolism Clinical和Experimental,41,Suppl.2,pp 76-79,1992);上胃肠出血(参见Jenkins,S.A.,等人,Gut.,33,pp.404-407,1992和Arrigoni,A.,等人,American Journal of Gastroenterology,87,p.1311,(abs.275),1992);假性胰腺囊肿和胰腺腹水(参见Hartley,J.E.,等人,J.Roy.Soc.Med.,85,pp.107-108,1992);白血病(参见Santini,等人,78,(Suppl.1),p.429A(Abs.1708),1991);脑膜瘤(参见Koper,J.W.,等人,J.Clin.Endocr.Metab.,74,pp.543-547,1992);和癌恶病质(参见Bartlett,D.L.,等人,Surg.Forum.,42,pp.14-16,1991)。
因此,本发明包括在其范围内的药物组合物,其含有作为活性成分、至少一种与药学上可接受的载体结合的式(I)的肽。
一般地,对于本发明活性成分的有效剂量,例如治疗肢端肥大症,范围是0.01至200mg/kg/天,优选0.5至100mg/kg/天。
本发明的肽可以经口服、非肠道的(例如,肌内的、腹膜内的、静脉内的或皮下注射或植入片)、鼻、***、直肠、舌下或局部途径给药,并且可与药学上可接受的载体配制以提供适于每种给药途径的剂型。
适于口服给药的固体剂型包括胶囊剂、片剂、丸剂、粉剂和颗粒剂。在这类固体剂型中,活性化合物与至少一种药学上可接受的惰性载体例如蔗糖、乳糖或淀粉混合。当为通常的惯例时,除了这样的惰性稀释剂外,这类剂型也可包括另外的物质,例如,润滑剂如硬脂酸镁。胶囊剂、片剂和丸剂情形下,这些剂型也包括缓冲剂。片剂和丸剂可另外以肠衣制备。
口服给药的液体剂型包括药学上可接受的乳剂、溶液、悬浮液、糖浆剂、酏剂,它们含有本领域通常使用的惰性稀释剂,例如水。除了这类惰性稀释剂之外,组合物亦包括助剂,例如润湿剂、乳化和悬浮剂,和增甜剂、调味剂以及香料。
按照本发明的非肠道的给药的制剂包括无菌水或非水溶液、悬浮液或乳剂。非水溶剂或载体的例子是丙二醇、聚乙二醇、植物油,例如橄榄油和玉米油、明胶以及可注射的有机酯,例如油酸乙酯。这类剂型也可含有助剂,例如防腐、润湿、乳化和分散剂。它们可以通过,例如,经留住细菌的滤器过滤,通过向组合物中掺入灭菌剂,通过照射组合物,或者通过加热组合物来灭菌。它们也可制备成无菌固体组合物的形式,这种形式在使用之前可以立即溶于无菌水,或一些其它的无菌可注射介质。
直肠或***给药的组合物优选是栓剂,除了活性物质之外,它含有赋形剂,例如可可油或栓剂蜡。
也可以以本领域公知的标准赋形剂制备鼻或舌下给药的组合物。
进一步地,本发明的化合物可以以持续释放组合物的形式给药,例如以下专利和专利申请描述的那些。美国专利No.5,672,659指出了含有生物活性剂和聚酯的持续释放组合物。美国专利No.5,595,760指出了含有生物活性剂的凝胶状的持续释放组合物。美国专利No.5,821,221指出了含有生物活性剂和壳聚糖的聚合的持续释放组合物。1996年11月1日提交的美国申请No.08/740,778指出了含有生物活性剂和环糊精的持续释放组合物。1998年1月29日提交的美国申请No.09/015,394指出了可吸收的含生物活性剂的持续释放组合物。1998年7月23日提交的美国申请No.09/121,653指出了一种以水包油方法制备含有例如肽的治疗剂的微粒的方法。1998年8月10日提交的美国申请No.09/131,472指出了含有例如肽的治疗剂和磷酰化(phosphorylated)聚合物的复合物。1998年11月2日提交的美国申请No.09/184,413指出了复合物,它含有例如肽的治疗剂以及含非聚合内酯的聚合物。前述专利和申请的指出内容一并引入本文作为参考。
本发明组合物中活性成分的剂量可以改变;然而,必需的是,活性成分的量是这样的以致于得到适当的剂型。选择的剂量取决于所需的治疗作用、给药途径和治疗期。一般地,给予人或其它动物,例如哺乳动物每天0.0001至100mg/kg体重之间的剂量水平,以得到生长激素的有效释放。
优选剂量范围是每天0.01至5.0mg/kg体重,它可以一次剂量或者分成多次剂量给药。
除非另有说明,本文使用的所有专业和科学术语具有如本发明所属领域普通熟练技术人员通常理解的同样含义。同样地,所有公开、专利申请、专利和其它本文提及的参考文献一并引入本文作为参考。
Claims (11)
1.一种下式(I)的肽,
X-A1-环(D-Cys-A3-A4-Lys-A6-A7)-A8-Y,
(I)
或其药学上可接受的盐,
其中
A1和A3每个独自选自以下组的氨基酸的D-或L-异构体:Phe、Tyr、Tyr(I)、Trp、3-Pal、4-Pal、Cpa和Nal;
A4是L-Trp、D-Trp、L-β-甲基-Trp或D-β-甲基-Trp;
A6是-NH-(CHR1)n-CO-,这里n是2、3或4;
A7是L-或D-Cys;
A8选自以下组的氨基酸的D-或L-异构体:Phe、Tyr、Tyr(I)、Trp、Nal、Cpa、Val、Leu、Iie、Ser和Thr;
Y是NR2R3,这里R2和R3每个独自是H或(C1-C5)烷基;
R1选自H、(C1-C4)烷基和-CH2-芳基;其中所述的芳基是选择性取代的部分,它选自苯基、1-萘基和2-萘基,其中所述的选择性取代部分是选择性地以一个或多个取代基取代,每个取代基独自选自以下基团:(C1-6)烷基、(C2-6)烯基、(C2-6)炔基、芳基、芳基(C1-6)烷基、(C1-6)烷氧基、-N(R4R5)、-COOH、-CON(R4R5)、卤素、-OH、-CN和-NO2;
R4和R5对于各自的情形,每个独自是H或(C1-3)烷基;
这里A2的Cys与A7的Cys通过由每个Cys的硫羟基形成的二硫键键合。
2.按照权利要求1的肽,其中
A1是L-Phe、D-Phe、L-Cpa或D-Cpa;
A3是L-Tyr、L-Trp或L-3-Pal;
A4是D-Trp;
A6是β-Ala或Gaba;
A7是L-Cys;
A8是L-Thr、L-Trp、L-Leu或L-Nal;和
R2和R3每个是H;
或其药学上可接受的盐。
3.按照权利要求2的肽,其中所述的肽具有下式:
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-β-Ala-Cys)-Nal-NH2;
Phe-环(D-Cys-3-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Phe-环(D-Cys-Trp-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Trp-NH2;
D-Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Nal-NH2;
D-Phe-环(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Leu-NH2;或
Phe-环-(D-Cys-Tyr-D-Trp-Lys-Gaba-Cys)-Thr-NH2;
或它们药学上可接受的盐。
4.按照权利要求3的肽,其中所述肽具有下式:
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-Gaba-Cys)-Nal-NH2;或
Cpa-环(D-Cys-3-Pal-D-Trp-Lys-β-Ala-Cys)-Nal-NH2;或它们药学上可接受的盐。
5.一种用于在人或其它动物中引起促生长素抑制素激动剂反应的药物组合物,它包括有效量的按照权利要求1的式(I)的肽或其药学上可接受的盐,以及药学上可接受的载体。
6.一种在人或其它动物中需要引起促生长素抑制素激动剂反应的方法,它包括给予人或其它动物有效量的按照权利要求1的式(I)的肽或其药学上可接受的盐。
7.一种在人或其它动物中选择性地结合促生长素抑制素亚型受体5型的方法,它包括给予人或其它动物有效量的按照权利要求1的式(I)的肽或其药学上可接受的盐。
8.一种对人或其它动物所需治疗疾病或病症的方法,它包括给予人或其它动物有效量的式(I)的肽或其药学上可接受的盐,其中所述的疾病或病症选自:库兴氏综合征、促性腺素瘤、甲状旁腺功能亢进、佩吉特氏疾病、VIP肿瘤、胰岛细胞增殖症、胰岛素分泌过多、促胃泌素瘤、卓林格-艾丽逊综合征、与AIDS和其它病症有关的分泌过多的腹泻、过敏性肠综合征、胰腺炎、克罗恩氏病、***性硬化症、甲状腺癌、牛皮癣、低血压、恐慌发作、硬皮病、小肠梗阻、胃食管回流、十二指肠胃回流、葛雷夫斯氏病、多囊卵巢疾病、上胃肠出血、假性胰腺囊肿、胰腺腹水、白血病、脑膜瘤、癌恶病质、肢端肥大症、再狭窄、肝细胞瘤、肺癌、黑素瘤、抑制快速生长的实体瘤、减轻体重、治疗胰岛素耐药性、综合征X、延长胰腺细胞存活、纤维样变性、高脂血症、高淀粉粒纤维素血症、高催乳素血症和催乳素血症。
9.一种在人或其它动物中所需抑制生长激素、胰岛素、胰高血糖素或胰腺外分泌物分泌的方法,它包括给予人或其它动物有效量的 1的式(I)的肽或其药学上可接受的盐。
10.一种在人或其它动物中对含促生长素抑制素受体的细胞进行体内造影的方法,它包括给予所述的人或其它动物权利要求1的式(I)的肽,条件是A1、A3或A8中的至少一个是Tyr(I),或其药学上可接受的盐。
11.一种对含促生长素抑制素受体的细胞进行体外造影的方法,它包括给予所述的人或其它动物权利要求1的式(I)的肽,条件是A1、A3或A8中的至少一种是Tyr(I),或其药学上可接受的盐。
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- 2000-06-23 JP JP2001506685A patent/JP4041311B2/ja not_active Expired - Fee Related
- 2000-06-23 IL IL14694100A patent/IL146941A0/xx unknown
- 2000-06-23 PL PL00352763A patent/PL352763A1/xx not_active Application Discontinuation
- 2000-06-23 AU AU62000/00A patent/AU770958B2/en not_active Ceased
- 2000-06-23 WO PCT/US2000/017401 patent/WO2001000676A1/en active IP Right Grant
- 2000-06-23 BR BR0011919-9A patent/BR0011919A/pt not_active Application Discontinuation
- 2000-06-23 EP EP00948520A patent/EP1189942A1/en not_active Ceased
- 2000-06-23 CA CA002377265A patent/CA2377265A1/en not_active Abandoned
- 2000-06-23 CN CN00811189A patent/CN1367792A/zh active Pending
- 2000-06-23 AR ARP000103155A patent/AR024463A1/es unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102725305A (zh) * | 2009-11-23 | 2012-10-10 | 帕拉丁科技公司 | 黑皮质素-1受体特异性环肽 |
CN102725305B (zh) * | 2009-11-23 | 2016-08-24 | 帕拉丁科技公司 | 黑皮质素-1受体特异性环肽 |
Also Published As
Publication number | Publication date |
---|---|
RU2263677C2 (ru) | 2005-11-10 |
MXPA01013127A (es) | 2002-11-04 |
BR0011919A (pt) | 2002-03-19 |
AU770958B2 (en) | 2004-03-11 |
AU6200000A (en) | 2001-01-31 |
HUP0201696A3 (en) | 2002-10-28 |
CA2377265A1 (en) | 2001-01-04 |
PL352763A1 (en) | 2003-09-08 |
JP4041311B2 (ja) | 2008-01-30 |
CZ20014534A3 (cs) | 2002-06-12 |
EP1189942A1 (en) | 2002-03-27 |
HUP0201696A2 (en) | 2002-09-28 |
IL146941A0 (en) | 2002-08-14 |
JP2003503369A (ja) | 2003-01-28 |
AR024463A1 (es) | 2002-10-02 |
WO2001000676A1 (en) | 2001-01-04 |
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