CN1088835A - 肽的应用 - Google Patents

肽的应用 Download PDF

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CN1088835A
CN1088835A CN93104504A CN93104504A CN1088835A CN 1088835 A CN1088835 A CN 1088835A CN 93104504 A CN93104504 A CN 93104504A CN 93104504 A CN93104504 A CN 93104504A CN 1088835 A CN1088835 A CN 1088835A
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glp
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oral hypoglycemic
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CN1072504C (zh
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O·科克
S·爱芬迪思
M·古尼克
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S Effendis
Novo Nordisk AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Abstract

GLP-1(7—37)、GLP-1(7—36)和某些相关化 合物能用于提供一种用于治疗以一定的饮食制度辅 以口服降血糖药治疗的糖尿病的药物。并观察到一 种强的协同作用。

Description

本发明涉及GLP-1（7-37）、GLP-1（7-36）氨化物/或某些相关化合物在制备用于以一定饮食制度辅以口服降血糖药，治疗糖尿病的药物上的用途。本发明也涉及用所说药物治疗糖尿病的方法。
糖尿病的特征是葡萄糖代谢作用降低，在糖尿病人中以高血糖水平表现出来。根据缺陷，糖尿病可分为两大类：Ⅰ型糖尿病或胰岛素依赖型糖尿病（IDDM）（当病人在其胰腺中缺乏产生胰岛素的β-细胞时发作）和Ⅱ型糖尿病或非胰岛素依赖型糖尿病（NIDDM）（除一系列其它异常外，发生在具有损坏的β-细胞功能的病人中。
Ⅰ型糖尿病人现在以胰岛素治疗，而多数Ⅱ型糖尿病人则以刺激β-细胞功能的药剂或提高病人对胰岛素组织敏感性的药剂治疗。
在使用的刺激β-细胞功能的药剂中，那些作用在β-细胞ATP-依赖钾通道上的药剂在现行的治疗方法中应用最广。所谓的磺酰脲类（例如，甲磺丁脲、优降糖、吡磺环己脲、甲磺吡脲（gliclazile）被广泛应用，其它作用在这种分子位点的药剂（例如AG-EE623ZW）正在开发中（AG-EE623ZW是对以下化合物的一个公司的编码：（S）-（+）-2-乙氧基-4-[2-[[3-甲基-1-[2-（1-哌啶基）苯基]丁基]-氨基]-2-氧乙荃]苯甲酸，欧洲专利公开号No.147，850（申请人Dr.Karl        Thomae        GmbH）中描述了该化合）。在使用的提高对胰岛素的组织敏感性的药剂中，二甲双胍是一个有代表性的例子。
尽管磺酰脲类被广泛用于治疗NIDDM，但这种治疗法在多数情况下是不令人满意的：在大量NIDDM病人中，磺酰脲不纯有效地使血糖水平正常化，因而病人患糖尿病并发症危险性大。而且，许多病人渐渐失去对磺酰脲治疗的应答能力，这样逐渐被迫使使用胰岛素治疗。这种从口服降血糖药到胰岛素治疗法的改变一般是由于NIDDM病人的β-细胞疲劳。
因此，过去的几年里人们做了很多尝试来提供刺激β-细胞功能的新药剂，以便给NIDDM病人一种改进的治疗。近来，一系列源于胰高血糖素样（glucagon-like）肽-1的肽类被以作是治疗使用的促胰岛素剂。
高血糖素样肽-1（也称作GLP-1）是一种存在于哺乳动物前（胰）高血糖素C-端部分的肽序列。1985年以前没有报道过GLP-1的特定生物活性，而1985年有人说明了GLP-1-一种片断的氨化物（称作GLP-1（1-36）氨化物）在有葡萄糖存在下，以一种剂量依赖方式刺激胰岛素从分离的预培养鼠胰岛（pancreatic        islets）释放（Schmidt，W.E等Diabetologia28（1985）704-7）。这一发现说明GLP-1（1-36）氨化物和相关的肽类可能在治疗Ⅱ型糖尿病方面有用。由于它实质上同源于胰高血糖素和葡萄糖依赖性促胰岛素肽（也称作GIP）的相近序列，Schmidt等人指出，GLP-1（7-36）表现出的胰高糖素和/或GIP样生物活性可能比完整的肽所表达的甚至更强。近年来人们的兴趣特别集中在GLP-1片断GLP-1（7-37）和GLP-1（7-36）氨化物和类似物和其功能性衍生物。代号GLP-1（1-36）指所述肽片断含有从母体肽（GLP-1）的N-端计数时的从第1个（包括第1个）到第36个（包括第36个）氨基酸残基。类似的，代号GLP-1（7-37）指所述肽片断含有从母体肽（GLP-1）的N端计数时的从第7个（包括第7个）到第37个（包括第37个）氨基酸残基。GLP-1（7-36）氨化物和GLP-1（7-36）的氨基酸序列由下式给出：
                            His-Ala-Gly-Thr-Phe-Thr-Ser-Asp-Val-
(Ⅰ)            Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-
                            Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X
当X是NH2时上式代表GLP-1（7-36）氨化物，当X是Gly-OH时上式代表GLP-（7-37）。
GLP-1（7-36）氨化物对人体是一种真正的促胰岛素剂，这一点已被Krecjmann，B.等说明，他们将这种肽注入到健康自愿者中去，观察到血浆胰岛素显著上升（Lancet        2（1987）1300-304）。
GLP-1（7-37）在糖尿病人和非糖尿病人中的促胰岛素作用已由Nathan，D.M等在Diabetes        Care        15（1992）270-76中说明。
国际专利申请No.WO        87/06941（申请人是The        General        Hospital        Corporation）涉及一种含有GLP-1（7-37）及其功能性衍生物的肽片断和它们作为促胰岛素剂的应用。
国际专利申请No.90/11296（申请人The        General        Hospital        Corporation）涉及一种含有GLP-1（7-36）及其功能性衍生物的肽片断（其促胰岛素活性超过GLP-1（1-36）或GLP-1（1-37）的促胰岛素活性）以及它们作为促胰岛素剂的应用。
国际专利申请No.91/11459（申请人Buckley等）涉及活性GLP-1肽7-34，7-35，7-36和7-37的有效类似物。
Parker，J.C.等（Diabetes        40（suppl.1）（1991）237A）在体外研究了GLP-1（7-37）与优降糖结合对鼠胰岛分泌胰岛素的作用。仅观察到两种药剂的加和作用。
然而，就本发明者所知，由一种口服降血糖药与一种GLP-1片断或一种类似物或其一种功能性衍生物结合使用所获得的惊人的体内协同作用从未见公开。
本发明基于惊人地发现当GLP-1相关肽一般与口服治疗Ⅱ型糖尿病的降血糖药（尤其是在治疗Ⅱ型糖尿病时与磺酰脲类）联合给药时，观察到一种协同作用。这种惊人的观察结果甚至在单用磺酰脲给药无反应的Ⅱ型糖尿病患者上被获得。
这样，从较宽的范围来说，本发明涉及GLP-1（7-37）、GLP-1（7-36）氨化物，或一种含有GLP-1（7-37）序列片断的药理上可接受的肽，或这一肽的一种类似物或一种功能性衍生物，在制备用于治疗以一定饮食制度辅以口服降血糖药治疗的Ⅱ型糖尿病的药物上的用途，并涉及治疗Ⅱ型糖尿病的方法，这一方法包括对有一定饮食制度并辅以口服降糖药的病人使用有效量的GLP-1（7-37）、GLP-1（7-36）氨化物，或一种含有GLP-1（7-37）序列片断的药理上可接受肽、或这一肽的类似物或功能性衍生物。
在第一优选实施方案中，本发明涉及GLP-1（7-36）氨化物在制备用于以一定饮食制度辅以口服降血糖药治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1（7-37）在制备用于以一定饮食制度辅以口服降血糖药治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一优选的实施方案中，本发明涉及GLP-1（7-37）的一种类似物在制备用于以一定饮食制度辅以口服降血糖药治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及一种GLP-1（7-37）功能性衍生物在制备用于以一定饮食制度辅以口服降血糖药治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生物在制备用于以一定饮食制度辅以甲磺丁脲治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选实施方案中，本发明涉及GLP-1（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生于在制备用物以一定饮食制度辅以优降糖治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1-（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生物在制备用于以一定饮食制度辅以吡磺环己脲治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生物在制备用于以一定饮食制度辅以甲磺吡脲（gliclazide）治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生物在制备用于以一定饮食制度辅以双胍治疗的Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生物在制备用于以一定饮食制度辅以二甲双胍治疗Ⅱ型糖尿病的治疗药物上的用途。
在另一个优选的实施方案中，本发明涉及GLP-1（7-37）或其一个片断或包括GLP-1（7-36）氨化物的这些物质中任何一个的类似物或功能性衍生物在制备用于以一定饮食制度辅以s-（+）-2-乙氧基-4-[2-[[3-甲基-1-[2-1-哌淀基）苯基]]基]-氨基]-2-氧乙基]苯甲酸治疗的Ⅱ型糖尿病的治疗药物上的用途。
在本说明书中，GLP-1（3-37）或GLP-1（3-36）氨化物的类似物分别指那些分别与GLP-1（3-37）或GLP-1（3-36）氨化物在以下不同之点的肽类：GLP-1（7-37）或GLP（7-36）氨化物分别有至少一个氨基酸残基独立地被另一个氨基酸残基所替换，优选的是能被基因密码编码的氨基酸替换，这种定义也包括氨基酸残基在肽的N-末端或C-末端增加或减少的情况。较好地是，这种增加，减少和替换的总数目不超过5，最好是不超过3。
如上所提及的，以磺酰脲类治疗的病人逐渐失去对磺酰脲治疗的反应，本领域人员一般接受的观点是：这种无效是由于β-细胞疲劳，它因此不能分泌胰岛素以应答葡萄糖刺激。人们一般也认为：磺酰脲类的功效受到β-细胞产生和分泌胰岛素能力的限制。因此，人们不能指望用磺酰脲类和其它刺激β-细胞功能的药剂治疗NIDDM病人会有什么额外的治疗上的优点。
NIDDM病人用GLP-1相关肽与磺酰脲类或其它口服降血糖药剂联合给药治疗可能是优越的，我们的这一发现因而将是惊人的。事实上我们已经发现，用口服降血糖药和GLP-1相关肽伴随治疗引起NIDDM病人协同反应：用口服降血糖药和GLP-1相关肽治疗引起的代谢反应较单独使用两种药剂引起的代谢反应总和要强。即使在磺酰胺脲无效的情况下，也发现该口服药剂明显提高GLP-1相关肽功效。
因此，用GLP-1相关肽和口服降血糖药联合治疗是全新的，治疗上有用的和惊人的。用两种类型药物治疗NIDDM病人能获得不可预见的治疗效果。
在能用于治疗Ⅱ型糖尿病的GLP-1相关肽中，GLP-1（3-37）和GLP-1（7-36）氨化物是特别优异的，因它的与天然产生的激素相似。包括部分GLP-1（7-37）序列的较短肽或这些较短肽的类似物或GLP-1（7-37）本身的类似物或以上任何一种的功能性衍生物也是优选使用的，因为可按照病人的需要通过修饰GLP-1相关片断来改变其药效学和药物动力学性质。
GLP-1相关肽可按本发明的现行可采用的肽的给药方法给药，从病人易于接受的观点看，鼻用给药特别有利。有关这一点的详细情况可查阅我们的末决丹麦专利申请No.DK        0364/92，该申请涉及包括GLP-1相关肽在内的药物经鼻给药，这一申请与本申请同时提交，所说申请的内容以整体形式并入此处作为参考。在需要活性肽特别在血浆中存留时间长延的情况下，注射或输液给药是优选的;在吸收范围和动力学不是关键因素的情况下，口头给药是优选的。
本发明使用的口服降血糖药可以是任何具有降低葡萄糖作用的口服药剂。在这些药剂中，那些作用在β-细胞ATP-依赖钾通道的药剂是优选的，例如：优降糖、吡磺环己脲、甲磺吡脲（gliclazide）和AG-EE623ZW。本发明的肽也可与其它口服药剂（例如二甲双胍）和相关化合物或象例如阿卞糖之类的葡糖苷酶抑制剂联合给药。
本发明说明书实施例和权利要求所公开的内容无论是它的分开的或合并的形成，均可以是从其不同形式认识本发明的材料。本发明进一步由下列实施例说明，这些实施例不用来限制本发明，只是用于说明本发明的一些优选的特征。
一般方法
血样品被收集到一个装有EDTA（0.048ml，0.34M和Trasylol（1000Iu血管舒缓素抑制剂，从西德Bager公司获得）的塑料管中并立即置入冰上。样品在4℃下离心，血浆在-20℃下贮藏，按照A.S.Hugger和D.A.Nixon（Lancet        2（1957）368-370）的葡萄糖氧化酶方法测定血糖。血浆C-肽浓度使用商业上购得的药盒（Novo        Research        Institute，Denmark）通过放射免疫测定法（RIA）测定血浆C-肽浓度。按G.R.Faloona和R.H.unger（in        B.M.        Jaffe        and        Behrman，eds.Methods        of        Hormone        Radioimmunoassay，Academic        Press，New        York（1974）317-330）所描述的使用抗体30K的RIA方法测定血浆胰高血糖素。
进一步的实验细节（如等血糖用餐相关胰岛素应答，IMIR的计算），可参考M.Gutmak，C.φrskoV，J.J.Holst，B，Ahren        and        S.efendic，The        New        England        Journal        of        Medicine        326（29）（1992）1316-1322，其中描述了在相似条件下完成的不同实验。
实施例1
GLP-1（7-36）氨化物和优降糖的协同作用。
在不同的4天里，在相同的由6个用胰岛素治疗的过度肥伴，NIDDM病人组成的病人组（体重指标：30.1±2.4）中研究了静脉注射1mg优降糖或输液给药GLP-1（7-36）氨化物（以每公开体重每分钟0.75pmol的速度或它们联合给药的作用，以盐水用药作对照。在待试化合物或盐水开始用药之前24小时停止胰岛素的常规给药，所有被试者禁食一夜。这一期间，用一种生物指示器（Biostator）（Miles，Diagnostic        Division，Elkhart，Ind.）进行胰岛素给药，以便在待试化合物给药之前使血糖水平正常，并且在食用标准试验餐180分钟后使饭后血糖分布保持正常。标准试验餐含有：煮土豆、煮牛肉、烧胡萝十一杯含有0.5%黄油的牛奶，一片小麦和黑麦混合面粉的烤面包。在这种餐食中，28、26和46%的能量分别来源于蛋白质，脂肪和碳水化合物。在达到血糖量正常30分钟后，待试化合物的用药分别完成（优降糖、盐水）或开始（GLP-1（7-36）氨化物）。输注GLP-1（7-36）氨化物持续210分钟。30分钟后，被试者在15分钟之内用完试验餐。
食入试验餐后，测定了用餐-相关C-肽应答，胰高血糖素应答和等血糖用餐-相关胰岛素需要量（IMIR）。结果列于表1。
表1
C - 肽应答pg/ml/210min 胰高血糖素应答pg/ml/210min IMIR(u)
对照（盐水）GLP-1(7-36)氨化物优降糖GLP-1（7－36）氨化物＋优降糖 7.4±3.625±9.8105±53.9184±55.1 269345±629910451±5126＊72526±4873 17.4±2.86.3±2.08.3±1.02.7±0.7
＊）优降糖对胰高血糖素释放没有明显影响。
从上表可见，GLP-1（7-36）氨化物和优降糖两者都明显增加用餐-相关C-肽应答（p＜0.02），当联合用药时发生明显的协同作用。GLP-1（7-36）氨化物抑制胰高血糖素应答（p＜0.01），而优降糖无明显作用，然而它与GLP-1（7-36）氨化物联合时胰高血糖素应答几乎消失。最后，优降糖和GLP-1（7-36）两者均降低IMIR，两者联合时IMIR低到2.7±0.7。
总之这一试验说明GLP-1（7-36）氨化物和优降糖联合有一种强的协同作用。

Claims (8)

1、GLP-1(7-37)、GLP-1(7-36)氨化物或一种含有GLP-1(7-37)序列片断的药理上可接受的肽，或这一肽的一种类似物或一种功能性衍生物在制备用于治疗以一定饮食制度辅以口服降血糖药治疗的糖尿病的药物上的用途。
2、按照权利要求1的GLP-1（7-37）或GLP-1（7-36）氨化物的用途。
3、按照权利要求1或2的用途，其中的口服降血糖药是β-细胞ATP-依赖钾通道阻断剂。
4、按照权利要求1或2的用途，其中的口服降血糖药是磺酰脲素。
5、按照权利要求1或2的用途，其中的口服降血糖药是（s）-（+）-2-乙氧基-地-[2-[[3-甲基-1-[2-（1-哌啶基）苯基]]基]-氨基-2-氧乙基]苯甲酸。
6、按照权利要求1或2的用途，其中的口服降血糖药是双胍。
7、按照权利要求1或2的用途，其中的口服降血糖药是二甲双胍。
8、一种治疗糖尿病的方法，包括对需要这种治疗的并已以一定的饮食制度辅以口服降血糖药治疗的病人使用有效的GLP-1（7-37）、GLP-1（7-36）氨化物或含有GLP-1（7-37）序列片断的药理学上可接受的肽，或这种肽的类似物或功能性衍生物。
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