CN114805487A - 一种多肽化合物及其应用 - Google Patents
一种多肽化合物及其应用 Download PDFInfo
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- CN114805487A CN114805487A CN202210634077.9A CN202210634077A CN114805487A CN 114805487 A CN114805487 A CN 114805487A CN 202210634077 A CN202210634077 A CN 202210634077A CN 114805487 A CN114805487 A CN 114805487A
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- alanine
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/04—Endocrine or metabolic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Food Science & Technology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Biotechnology (AREA)
- Physics & Mathematics (AREA)
- Cell Biology (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Polymers & Plastics (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了一种多肽化合物及其应用,多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构,所述式I为:U1‑A1‑A2‑A3‑U2‑W‑R1。实验结果表明,本发明提供的多肽化合物对GHSR‑1a具有较高的激动活性,毒副作用小,在血浆中具有较好的稳定性,具有成为临床候选化合物的潜力。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种多肽化合物及其应用。
背景技术
生长激素(growth hormone,GH)是由脑垂体促生长激素细胞释放,主要刺激组织的生长,同时影响代谢过程,在能量代谢中影响碳水化合物到脂肪酸代谢的交换。生长激素的释放受两种下丘脑神经肽的调控,两种下丘脑神经肽分别为促进释放的生长激素释放激素(growth hormone releasing hoemone,GHRH)和抑制释放的生长激素释放抑制激素(Somatostatin,SS)。
生长激素释放肽(ghrelin)是生长激素促分泌素受体(growth hormonesecretagogue receptor,GHSR)的内源性配体。生长激素促分泌激素受体(Growth HormoneSecretagogue Receptor,GHSR),也被称为胃饥饿素受体,从猪垂体的cDNA库被成功筛选分离,是由7个跨膜α螺旋组成的G蛋白偶联受体,调控促生长激素细胞中生长激素的释放。GHSR的结构编码基因组在不同物种中高度保守,按不同的外显子编码分为1a型和1b型,其中GHSR-1a是胃饥饿素(Ghrelin)的功能性受体,该受体与Ghrelin结合后激活磷脂酶C(PLC)、三磷酸肌醇(IP3)、甘油二酯(DAG)、蛋白激酶C(PKC)等发挥生物学效应,而非功能性受体GHSR-1b无生物学活性。在调节GH分泌的系统中,GHRH与其受体结合,启动AC/cAMP/PKA通道,增加细胞内环磷酸腺苷的水平;ghrelin与其受体结合,K+通道的去极化和抑制,引起细胞内IP3浓度升高,细胞内的Ca2+浓度升高,最终刺激GH的分泌,SRIF通过阻碍第二信使cAMP的合成来抑制GH分泌。GH从促生长激素细胞的释放也受到GHRP的控制。已有发现六肽GHRP6在包括人的几种物种中以剂量依赖性方式调节促生长激素细胞中释放生长激素(Bowers et al.,Endocrinology,1984,114,1537-1545)。
通过分析GHRP6的结构,发现了一些GHRP类似物,可以与GHSR-1a结合,产生激动活性,引起信号转导,调节生长激素的分泌,但在临床开发上均具有一定的局限性。因此,开发具有活性高、剂量小以及低毒副作用的分子结构是GHSR-1a受体激动剂的研究目标,在保留或提高多肽的生理活性的同时,保持多肽的稳定性,是行之有效的药物开发策略之一。
发明内容
有鉴于此,本发明的目的在于提供一种多肽化合物及其应用,多肽化合物具有较高的GHSR-1a激动活性,同时在血浆中具有较高的稳定性。
为实现上述目的,本发明的技术方案为多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构:
U1-A1-A2-A3-U2-W-R1 式I;
其中,R1为-NR2R3,-OR2或-SR2;
并且,R1不为D型或L型氨基酸残基;
R2和R3相互独立地为氢、氘、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基;在一个实施例中,R2和/或R3为取代的或未经取代的非环状脂族基团,优选为取代的或未经取代的线性或支化的烷基;
W为单键、D型氨基酸残基或L型氨基酸残基;
U1选自以下任意一种结构:
其中,X和Z相互独立地选自以下任意一种结构:
其中R4和R12相互独立地为氢、氘、氨基、保护性基团、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基或R5CO-;在一个实施例中,R4和/或R12为取代的或未经取代的非环状脂族基团,优选为取代的或未经取代的线性或支化的烷基;
R5为氢、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基;在一个实施例中,R5为取代的或未经取代的非环状脂族基团,优选为取代的或未经取代的线性或支化的烷基;
Y和R11相互独立地为氢、氨基、硝基、羟基、卤素、氰基、胺甲基、胺乙基、胺丙基或胺丁基;
m1、m2、m3和m4相互独立地为0,1,2或3;
n1、n2、n3和n4相互独立地为0,1,2或3;
U2为以下结构,且U2的羰基端与W连接:
其中,R6为氢、氘、保护性基团、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基;在一个实施例中,R6为取代的或未经取代的非环状脂族基团,优选为取代的或未经取代的线性或支化的烷基;
R7选自以下任意一种结构:
其中R8和R13相互独立地为氢、氘、氨基、保护性基团、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基或R9CO-;在一个实施例中,R8和/或R13为取代的或未经取代的非环状脂族基团,优选为取代的或未经取代的线性或支化的烷基;
R9为氢、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基;在一个实施例中,R9为取代的或未经取代的非环状脂族基团,优选为取代的或未经取代的线性或支化的烷基;
p和q相互独立地为0、1、2、3、4或5;
A1为D型或L型氨基酸残基,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、鸟氨酸、3-(2-吡啶基)-丙氨酸、3-(3-吡啶基)-丙氨酸、3-(4-吡啶基)-丙氨酸、苯丙氨酸、4,4'-联苯丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、2'-(4-苯基)-咪唑基、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸、3-(4-喹啉基)-丙氨酸、3-(4-噻唑基)-丙氨酸、3-(2-噻吩基)-丙氨酸、3-(3-噻吩基)-丙氨酸、3-(1H-吡咯并[2,3-b]吡啶-3-基)丙氨酸或O-苄基-苏氨酸;
A2为D型或L型氨基酸残基,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、鸟氨酸、3-(2-吡啶基)-丙氨酸、3-(3-吡啶基)-丙氨酸、3-(4-吡啶基)-丙氨酸、苯丙氨酸、4,4'-联苯丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、2'-(4-苯基)-咪唑基、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸、3-(4-喹啉基)-丙氨酸、3-(4-噻唑基)-丙氨酸、3-(2-噻吩基)-丙氨酸、3-(3-噻吩基)-丙氨酸、3-(1H-吡咯并[2,3-b]吡啶-3-基)丙氨酸或O-苄基-苏氨酸;
其中,A1为3-(3-苯并噻吩基)-丙氨酸残基,A2不为3-(3-吲哚基)丙氨酸残基;
A3为D型或L型氨基酸,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、鸟氨酸、3-(2-吡啶基)-丙氨酸、3-(3-吡啶基)-丙氨酸、3-(4-吡啶基)-丙氨酸、苯丙氨酸、4,4'-联苯丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、2'-(4-苯基)-咪唑基、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸、3-(4-喹啉基)-丙氨酸、3-(4-噻唑基)-丙氨酸、3-(2-噻吩基)-丙氨酸、3-(3-噻吩基)-丙氨酸、3-(1H-吡咯并[2,3-b]吡啶-3-基)丙氨酸或O-苄基-苏氨酸。
在一个实施例中,本发明所述多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构,其中,A1、A2、A3、U2、W和R1如式I所示,在此不再赘述,U1选自以下任意一种结构:
其中,Y和R11如式I所示,在此不做赘述。
在一个实施例中,本发明所述多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构,其中,U1、A1、A2、A3、W和R1如式I所示,在此不再赘述,U2为以下结构:
其中,R6为氢、取代或未取代的甲基、取代或未经取代的乙基、取代或未经取代的丙基、取代或未经取代的异丙基、取代或未经取代的丁基、取代或未经取代的异丁基、取代或未经取代的叔丁基;所述取代的甲基、取代的乙基、取代的丙基、取代的异丙基、取代的丁基、取代的异丁基和取代的叔丁基中取代基相互独立地为卤素、氨基、硝基、羟基、甲酰胺基、乙酰胺基、丙酰胺基、丁酰胺基、脲基或胍基。
在一个实施例中,本发明所述多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构,其中,R1为-NR2R3或-OR2,其中R2和R3相互独立地为氢、甲基、乙基、己基、十二烷基或十六烷基,U1、A1、A2、A3、U2和W如式I所示,在此不再赘述。
在一个实施例中,本发明所述多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构,其中,W为单键、丙氨酸残基、精氨酸残基、天冬酰胺残基、半胱氨酸残基、谷氨酰胺残基、天冬氨酸残基、谷氨酸残基、甘氨酸残基、组氨酸残基、异亮氨酸残基、亮氨酸残基、赖氨酸残基、甲硫氨酸残基、苯丙氨酸残基、脯氨酸残基、丝氨酸残基、苏氨酸残基、色氨酸残基、酪氨酸残基或缬氨酸残基;U1、A1、A2、A3、U2和R1如式I所示,在此不再赘述。
在一个实施例中,本发明所述多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构,其中,A1为D型或L型氨基酸残基,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸或3-(4-喹啉基)-丙氨酸;
A2为D型或L型氨基酸,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸或3-(4-喹啉基)-丙氨酸;
A3为D型苯丙氨酸残基或L型苯丙氨酸残基;
U1、U2、W和R1如式I所示,在此不再赘述。
在一个实施例中,本发明所述多肽化合物或其立体异构体、药学上可接受的盐,具有以下任意一种结构:
实验结果表明,本发明所述多肽化合物或其立体异构体、药学上可接受的盐具有GHSR-1a激动剂活性、成药安全性和血浆稳定性。
本发明提供的多肽化合物C端的氨基酸残基中刚性结构或柔性结构的大小对于维持序列中肽键的构型至关重要,进而,本发明通过在序列C端进行不同结构类型官能团的引入,使多肽化合物可以有效地与GHSR-1a结合,并将多肽化合物用于治疗、预防、减轻或诊断由GHSR-1a介导的紊乱所致相关疾病。
本发明所述多肽化合物或其立体异构体、药学上可接受的盐的合成方法为现有技术已知的任何常规方法,本发明在此不做限定,所述合成方法可以为固相肽合成方法[Stewart J.M.y Young J.D.,“Solid Phase Peptide Synthesis,2nd edition”,(1984),Pierce Chemical Compa ny,Rockford,Illinois;Bodanzsky M.y Bodanzsky A.,“Thepractice of Peptide Synthesis”,(1994),Springer Verlag,Berlin;Lloyd WilliamsP.et al.,“Chemical Approaches to the Synthesis of Peptides and Proteins”,(1997),CRC,Boca Raton,FL,USA]、液相合成方法、酶促合成方法[Kullmann W.“Proteasesas catalysts for enzymic syntheses of opioid peptides”,(1980),J.Biol.Chem.,255(17),8234-8238]或现有技术任意组合的方法。本发明所述多肽化合物还可以由目的在于产生所希望序列的基因工程修饰的或未修饰的细菌菌株的发酵来获得,或者,由动物、真菌或优选植物来源的蛋白的游离含有至少所希望序列的肽段的受控水解来获得。
在一个实施例中,可以采用编码加本文所述的多肽氨基酸序列的核酸序列以及任选地进行适当的氨基酸修饰来得到本发明的化合物。
在一个实施例中,本发明所述多肽化合物或其立体异构体、混合物的合成方法包括以下步骤:
1)将N-末端保护的和C-末端游离的氨基酸与N-末端游离的和C-末端保护或结合至固体载体的氨基酸偶联;
2)消除保护N-末端的基团;
3)重复偶联程序并且消除保护N-末端的基团直至获得所希望的肽序列;
4)消除保护C-末端的基团或裂解固体载体。
在一个实施例中,将C-末端结合至固体载体上并且该过程在固相中进行,将N-末端保护的和C-末端游离的氨基酸与N-末端游离的和C-末端结合至聚合物载体的氨基酸偶联;消除保护N-末端的基团;按必要次数重复偶联程序并且消除保护N-末端的基团以获得所希望长度的化合物;裂解最初的固体载体上合成的化合物,得到多肽化合物。
在合成过程中,氨基酸侧链的官能团保持用暂时或永久保护性基团方便地保护,并且能够与从聚合物载体裂解肽的过程同时地或正交地脱保护。
另选地,固相合成可以用会聚策略进行:将肽与聚合物载体偶联或者与预先结合至聚合物载体的肽或氨基酸偶联。会聚合成策略是本领域技术人员广泛已知的并且描述于Lloyd-Williams P.et al.,“Convergent Solid-Phase Peptide Synthesis”,(1993),Tetrahedron,49(48),11065-11133。
本发明采用的合成方法过程中,在采用现有技术已知的标准程序和条件的情况下,能够以无差别顺序包括额外的C-末端脱保护和/或从聚合物载体裂解肽的阶段;在此之后这些末段官能团能够加以修饰。在式I所示多肽化合物固定至聚合物载体时或一旦多肽化合物已从聚合物载体分开,则能够进行C-末端的任选修饰。
任选地和/或额外地,本发明中R1残基可以以以下方法引入:在适当溶剂和碱比如N,N-二异丙基乙胺(DIEA)或三乙胺或添加剂比如1-羟基苯并三唑(HOBt)或1-羟基氮杂苯并三唑(HOAt)和脱水剂比如碳二亚胺、脲鎓盐、鏻盐或脒鎓盐等存在下,将化合物HR1,其中R1可以是-OR2、-NR2R3或-SR2,与互补片段相应于式I化合物发生反应,其中R1可以是-NH2;或者通过先将互补片段相应于式I化合物与例如亚硫酰氯预先形成酰卤,再与HR1发生反应,由此获得化学式I的根据本发明的肽,其中片段具有并不牵涉于N-C键形成中官能团用暂时或永久保护性基团加以适宜保护;或者另选地其它R1残基可以通过同时掺入肽从聚合物载体裂解的过程来引入。
本领域技术人员会容易地理解C-末端和N-末端的脱保护/裂解步骤和随后的衍生化过程能够根据现有技术已知的过程以不同顺序进行。
本发明所述多肽化合物的药学上可接受的盐能够通过现有技术中熟知的常规方法获得(Berge S.M.et al.,“Pharmaceutical Salts”,(1977),J.Pharm.Sci.,66,119,其通过引用整体并入本文)。
本发明还提供了一种组合物,包括多肽化合物或其立体异构体、药学上可接受的盐中的一种或多种;可接受的辅料。
本发明所述组合物可以为药物组合物,也可以为保健品组合物,本发明在此不做限定。本发明所述组合物中,多肽化合物可以单独存在,或两种及两种以上混合存在,或通过复合、结晶或离子键合或共价键合更紧密地缔合。
本发明所述辅料包括但不限于本领域技术人员熟知的载体、稀释剂、赋形剂或辅助剂。在一个实施例中,本发明所述辅料为载体,载体包括但不限于无菌水、盐水、缓冲液、磷酸缓冲盐水、缓冲氯化钠、植物盐、最小必需培养基(MEM)或具有HEPES的MEM。
本发明还提供了多肽化合物或其立体异构体、药学上可接受的盐在制备生长激素促分泌素受体的激动剂中的应用,或在制备用于治疗、预防、减轻和/或诊断由生长激素促分泌素受体介导的紊乱所致相关疾病的药物中的应用,或在制备促进生长发育的保健品中的应用。
在一个实施例中,本发明所述生长激素促分泌素受体的激动剂为GHSR-1a激动剂。
在一个实施例中,本发明所述由生长激素促分泌素受体介导的紊乱所致相关疾病为生长激素缺乏症。
本发明所述多肽化合物或其立体异构体、药学上可接受的盐制成的生长激素促分泌素受体的激动剂,可以以多种方式施用,施用方式取决于期望局部施用还是全身性施用并且取决于待治疗的区域。在一个实施例中,可经过以下方式向患者施用所述多肽化合物或其组合物或其GHSR-1a激动剂:口腔或直肠、或经粘膜、或肠内、或肌内、或皮下、或髓内、或鞘内、或直接心室内、或静脉内、或玻璃体内、或腹膜内、或鼻内、或眼内。
本发明还提供了一种组合物在制备生长激素促分泌素受体的激动剂中的应用,或在制备用于治疗、预防、减轻和/或诊断由生长激素促分泌素受体介导的紊乱所致相关疾病的药物中的应用,或在制备促进生长发育的保健品中的应用。
本发明中,所述术语“保护性基团”涉及阻塞有机官能团的和能够在受控条件下除去的基团,术语“保护性基团”也包括固相合成中的聚合物载体。所述保护性基团及其相对反应性和保持惰性的条件是本领域技术人员已知的。
氨基基团的代表性保护性基团的实例是酰胺乙酸酯,酰胺苯甲酸,酰胺特戊酸脂;氨基甲酸酯类比如苄氧基羰基(Cbz或Z),2-氯苄基(CIZ),对-硝基苄氧基羰基(pNZ),叔丁氧基羰基(Boc),2,2,2-三氯乙氧羰基(Troc),2-(三甲基甲硅烷基)乙基氧基羰基(Teoc),9-芴基甲基氧基羰基(Fmoc)或烯丙基氧基羰基(Alloc),三苯甲基(Trt),甲氧基三苯甲基(Mtt),2,4-二硝基苯基(Dnp),N-1-(4,4-二甲基-2,6-二氧代环己-1-亚基)乙基(Dde),1-(4,4-二甲基-2,6-二氧代-亚环己基)-3-甲基丁基(ivDde),1-(1-金刚烷基)-1-甲基乙氧基羰基(Adpoc),优选Boc或Fmoc。
羧基基团代表性保护性基团的实例是酯,比如叔丁基酯(tBu),烯丙基酯(All),三苯基甲基酯(Trt酯),环己基酯(cHx),苄基酯(Bzl),邻硝基苄基酯,对硝基苄基酯,对甲氧基苄基酯,三甲基甲硅烷基乙基酯,2-苯基异丙基酯,芴基甲基酯(Fm),4-(N-[1-(4,4-二甲基-2,6-二氧代-亚环己基)-3-甲基丁基]氨基)苄基酯(Dmab),优选All,tBu,cHx,Bzl和Trt酯。
含有三官能团氨基酸的侧链能够在合成过程期间用与N-末端和C-末端保护性基团正交的暂时或永久保护性基团加以保护。
色氨酸侧链的吲哚基团能够通过甲酰基基团(For),Boc,Mts保护或者能够不加保护地使用。4-氨基-4-哌啶甲酸侧链的哌啶基团通过Boc或Fmoc保护。精氨酸侧链可以通过以下保护性基团保护:Tos,4-甲氧基-2,3,6-三甲基苯磺酰基(Mtr),Alloc,硝基,2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基(Pbf)和2,2,5,7,8-五甲基色满-6-磺酰基(Pmc)。为了保护赖氨酸和鸟氨酸侧链的氨基基团能够使用酰胺,比如乙酸酰胺,苯甲酸酰胺,特戊酸酰胺;氨基甲酸酯类比如Cbz或Z,CIZ,pNZ,Boc,Troc,Teoc,Fmoc或Alloc,Trt,Mtt,Dnp,Dde,ivDde,Adpoc等。
在一个实施例中,氨基酸采用的保护性基团如下所述:氨基基团通过Boc保护,羧基基团通过Bzl、cHx或All保护,精氨酸侧链通过Tos保护,4-氨基-4-哌啶甲酸侧链的哌啶基团通过Fmoc保护,色氨酸侧链通过For或Mts保护、Apc赖氨酸和鸟氨酸侧链通过CIZ、Fmoc或Alloc保护。
在一个实施例中,氨基酸采用的保护性基团如下所述:氨基基团通过Fmoc保护,羧基基团通过tBu、All或Trt酯保护,精氨酸侧链通过Pmc或Pbf保护,4-氨基-4-哌啶甲酸侧链的哌啶基团通过Boc保护,色氨酸侧链通过Boc保护或未加保护地使用,赖氨酸和鸟氨酸侧链通过Boc、Trt或Alloc保护。
保护性基团的的引入和除去,能够参考文献[Atherton B.and Sheppard R.C.,“Solid Phase Peptide Synthesis:A practical approach”,(1989),IRL OxfordUniversity Press]。
在合成完全或部分发生在固相中的情况下,用于本发明过程中的固体载体包括但不限于聚苯乙烯载体、接枝至聚苯乙烯的聚乙二醇,比如且不限于对甲基二苯甲基桉树酯(MBHA)[Matsueda G.R.et al.,“A p-methyl benzhydrylamine resin for improvedsolid-phase synthesis of peptide amides”,(1981),Peptides,2,4550]、2-氯三苯甲基树脂[Barlos K.et al.,“Darstellung geschützter PeptidFragmente unter Einsatzsubstituierter Triphenylmethyl Harze”,(1989),Tetrahedron Lett.,30,3943-3946;Barlos K.et al.,“Veresterung von partiell geschützten PeptidFragmenten mitHarzen Einsatz von 2-Chlorotritylchlorid zur Synthese von LeulGastrin I”,(1989),Tetrahedron Lett.,30,39473951]、树脂(Rapp Polymere GmbH)、树脂(Matrix Innovation,Inc),所述固体载体可以包括不稳定连接体,如5-(4-氨甲基-3,5-二甲氧基苯氧基)戊酸(PAL)[Albericio F.et al.,“Preparation andapplication of the 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethy l-3,5-dimethoxy-phenoxy)valeric acid(PAL)handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions”,(1990),J.Org.Chem.,55,3730-3743]和2-[4-氨甲基-(2,4-二甲氧基苯基)]苯氧基乙酸(AM)[Rink H.,“Solid-phasesynthesis of protected peptide fragments using a trialkoxy–diphenyl-methylester resin”,(1987),Tetrahedron Lett.,28,3787-3790],Wang[Wang S.S.,“p-Alkoxybenzyl Alcohol Resin and p-Alkoxybenzyl oxycarbonylhydrazide Resin forSolid Phase Synthesis of Protected Peptide Fragments”,(1973),J.Am.Chem.Soc.,95,1328-1333],其使得可以同时脱保护和从聚合物载体裂解肽。
定义
在本发明中使用的缩写具有下面的含义:
Ala(Alanine,A)丙氨酸
Aba(2-aminobutyric acid)2-氨基丁酸
Arg(Arginine,R)精氨酸
Bal(3-Benzothienylalanine)3-苯并噻吩基丙氨酸
Boc(butyloxycarboryl)叔丁氧羰基
Cit(Citrulline)瓜氨酸
DCM(Dichloromethane)二氯甲烷
DIEA(N,N-Diisopropylethylamine)N,N-二异丙基乙胺
DMF(N,N-Dimethylformamide)N,N-二甲基甲酰胺
Fmoc(Fluorenylmethoxycarbonyl)芴甲氧羰基
Gly(Glycine,G)甘氨酸
HBTU(O-Benzotriazole-N,N,N',N'–tetraMethyl–uroniuM–hexafluorophosphate)O-苯并三氮唑-四甲基脲六氟磷酸酯
HOBt(N-Hydroxybenzotrizole)1-羟基苯并三唑
HPLC(High performance liquid chromatography)高效液相色谱
Leu(Leucine,L)亮氨酸
Lys(Lysine,K)赖氨酸
Nle(Norleucine)正亮氨酸
Orn(Ornithine)鸟氨酸
Phe(Phenylalanine,F)苯丙氨酸
Pro(Proline,P)脯氨酸
TFA(Trifluoroacetic acid)三氟乙酸
Tle(Tertiary leucine)叔亮氨酸
Trp(Tryptophan,W)色氨酸
Val(Valine,V)缬氨酸
如本文所定义的,术语“多肽”,“肽”和“氨基酸序列”在本文中可互换使用,是指任何长度的氨基酸残基的聚合物。该聚合物可以是直链或支链的,它可以包含修饰的氨基酸或氨基酸类似物,并且可以被非氨基酸的化学部分打断。该术语还包括已被天然或人工修饰(例如二硫键形成,糖基化,脂化,乙酰化,磷酸化或任何其他操作或修饰,例如与标记或生物活性组分缀合)的氨基酸聚合物。术语“肽”包括通过共价键(例如酰胺键)连接的两个或更多个天然存在的或合成的氨基酸。
在本公开内容的上下文中,术语“氨基酸”被定义为具有至少一个伯、仲、叔或季氨基和至少一个酸基,其中酸基可以是羧酸、磺酸或磷酸或其混合物。氨基相对于酸基可以是“α”、“β”、“γ”至“ω”。合适的氨基酸包括但不限于在肽中发现的20种常见天然存在的氨基酸(例如丙氨酸,精氨酸,天冬酰胺,半胱氨酸,谷氨酰胺,天冬氨酸,谷氨酸,甘氨酸,组氨酸,异亮氨酸,亮氨酸,赖氨酸,甲硫氨酸,苯丙氨酸,脯氨酸,丝氨酸,苏氨酸,色氨酸,酪氨酸,缬氨酸)的D型和L型异构体以及通过有机合成或其他代谢途径制备的天然存在的和非天然存在的氨基酸。
术语“氨基酸残基”被定义为术语“氨基酸”氨基酸通过氨基或羧基反应,形成多肽后的残基。
术语“氨基酸的主链”可以被选自卤素、羟基、胍基、杂环基团的一个或多个基团取代。因此术语“氨基酸”在其范围内还包括甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,正亮氨酸,甲硫氨酸,脯氨酸,苯丙氨酸,色氨酸,丝氨酸,苏氨酸,半胱氨酸,酪氨酸,天冬酰胺,谷氨酰胺,天冬氨酸,谷氨酸,赖氨酸,组氨酸,高半胱氨酸,牛磺酸,甜菜碱,N-甲基丙氨酸等。L型和D型的氨基酸被包括在内。
术语“氨基酸侧链”是指连接至氨基酸的α-碳的部分。例如,丙氨酸的氨基酸侧链是甲基,苯丙氨酸的氨基酸侧链是苯基甲基,半胱氨酸的氨基酸侧链是硫代甲基,天冬氨酸的氨基酸侧链是羧甲基,酪氨酸的氨基酸侧链是4-羟基苯甲基,等等。还包括其他非天然存在的氨基酸侧链,例如天然存在的(例如氨基酸代谢物)或合成制备的(例如α-取代的氨基酸)。
本发明中术语“非环状脂族基团”包括线性或支化的烷基,烯基和炔基基团。
术语“烷基”是指线性或支化的饱和基团,其具有1至24,优选1至16,更优选1至14,甚至更优选1至12,还更优选1、2、3、4、5或6个碳原子和通过简单键结合至分子其余部分,包括但不限于,甲基,乙基,异丙基,异丁基,叔丁基,庚基,辛基,癸基,十二烷基,月桂基,十六烷基,十八烷基,戊基,2-乙基己基,2-甲基丁基和5-甲基己基。
术语“烯基基团”是指线性或支化的基团,其具有2至24,优选2至16,更优选2至14,甚至更优选2至12,还更优选2、3、4、5或6个碳原子,具有一个或多个碳-碳双键,优选具有1,2或3个碳-碳双键,键是共轭或不共轭的,其通过简单键合至分子其余部分,包括但不限于乙烯基(-CH2=CH2),烯丙基(-CH2-CH=CH2),油烯基和亚油烯基。
术语“炔基基团”是指线性或支化的基团,其具有2至24,优选2至16,更优选2至14,甚至更优选2至12,还更优选2、3、4、5或6个碳原子,具有一个或多个碳-碳三键,优选具有1,2或3个碳-碳三键,键是共轭或不共轭的,其通过简单键合至分子其余部分,包括例如但不限于乙炔基基团,1-丙炔基,2-丙炔基,1-丁基,2-丁基,3-丁基,戊基,比如1-戊基。炔基基团还能够含有一个或多个碳-碳双键,包括但不限于基团丁-1-烯-3-炔基和戊-4-烯-1-炔基。
术语“脂环基基团”在本发明中用于涵盖例如且不限于环烷基或环烯基或环炔基基团。
术语“环烷基”是指饱和的单环或多环脂族基团,其具有3至24,优选3至16,更优选3至14,甚至更优选3至12,还更优选3、4、5或6个碳原子并且通过简单键结合至分子其余部分,包括但不限于,环丙基,环丁基,环戊基,环己基,环庚基,甲基环己基,二甲基环己基,八氢茚,十氢萘和十二氢非那烯。
术语“环烯基”是指非芳族单环或多环脂族基团,其具有5至24,优选5至16,更优选5至14,甚至更优选5至12,还更优选5至6个碳原子,具有一个或多个碳-碳双键,优选1,2或3个碳-碳双键,键是共轭或不共轭的,其通过简单键合至分子其余部分,包括但不限于环戊-1-烯-1-基基团。
术语“环炔基”是指非芳族单环或多环脂族基团,其具有8至24,优选8至16,更优选8至14,甚至更优选8至12,还更优选8或9个碳原子,具有一个或多个碳-碳三键,优选1,2或3个碳-碳三键,键是共轭或不共轭的,其通过简单键合至分子其余部分,包括但不限于环辛-2-炔-1-基基团。环炔基基团还能够含有一个或多个碳-碳双键,包括但不限于环辛-4-烯-2-炔基基团。
术语“芳基基团”是指芳族基团,其具有6至30,优选6至18,更优选6至10,还更优选6或10个碳原子,其包含1、2、3或4个芳族环,通过碳-碳键结合或稠合,包括但不限于苯基,萘基,二苯基,茚基,菲基或蒽基;或者芳烷基基团。
术语“芳烷基”是指被芳族基团取代的烷基,具有7至24个碳原子和包括例如且不限于-(CH2)1~6-苯基、-(CH2)1~6-(1-萘基)、-(CH2)1~6-(2-萘基)、-(CH2)1-6-CH(苯基)2以及类似物。
术语“杂环基基团”是指3-10元的烃化的环,其中环中原子的一个或多个,优选环中原子的1、2或3个是不同于碳的元素比如氮、氧或硫,并且可以是饱和或不饱和的。杂环能够是单环、双环或三环系统,其可以包括稠环系统;和残基杂环中的氮、碳或硫原子可以被任选地氧化;氮原子可以被任选地季铵化;和残基杂环基可以是部分或完全饱和的或是芳族的。术语杂环基优选5或6元环。饱和的杂环基基团的实例是二噁烷,哌啶,哌嗪,吡咯烷,吗啉和硫吗啉。芳族杂环基基团,也称为杂芳族基团的实例是吡啶,吡咯,呋喃,噻吩,苯并呋喃,咪唑啉,对苯二酚,喹啉和萘啶。
术语“杂芳基烷基基团”是指被取代的或未经取代的芳族杂环基基团取代的烷基,烷基具有1至6个碳原子和芳族杂环基基团具有2至24个碳原子和1至3个非碳的原子,并且包括例如且不限于-(CH2)1~6-咪唑基、-(CH2)1~6-三唑基、-(CH2)1~6-噻吩基、-(CH2)1~6-呋喃基和-(CH2)1~6-吡咯烷基。
本文使用的术语“卤素”、“卤化物”或“卤代”是指氟、氯、溴和碘。
如本文所用的术语“杂原子”或“杂-”是指O、N、NH和S。
如本文所用的术语“烷氧基”是指直链或支链烷氧基。实例包括甲氧基,乙氧基,正丙氧基,异丙氧基和叔丁氧基。
如本文所用的术语“氨基”是指-NRaRb形式的基团,其中Ra和Rb独立地选自包括但不限于氢、任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的芳基的组。
应理解,如本文所述的本发明的化合物均可被任何数目的取代基或官能团部分取代。通常,术语“(经)取代(的)”(无论其是否在术语“任选地”之后)和含于本发明的式中的取代基都是指用指定取代基的基团对给定结构中的氢基的替代。当任何给定结构中的超过一个位置可被超过一个选自指定基团的取代基取代时,所述取代基在每个位置可相同或不同。如本文所用的术语“经取代的”预期包括用有机化合物的所有可允许取代基、本文所述的任何取代基进行的取代。
例如,取代基包括但不限于导致形成稳定部分的以下基团:脂肪族基、烷基、烯基、炔基、杂脂肪族基、杂环基、芳基、杂芳基、酰基、氧代、亚氨基、硫羰基、氰基、异氰基、氨基、叠氮基、硝基、羟基、硫醇基和卤代以及它们的任何组合,包括但不限于以下基团:脂肪族氨基、杂脂肪族氨基、烷基氨基、杂烷基氨基、芳基氨基、杂芳基氨基、烷基芳基、芳基烷基、脂肪族氧基、杂脂肪族氧基、烷氧基、杂烷氧基、芳氧基、杂芳氧基、脂肪族硫基、杂脂肪族硫基、烷硫基、杂烷硫基、芳硫基、杂芳硫基、酰氧基等。本发明涵盖任何和所有的此类组合以得到稳定的取代基/部分。出于本发明的目的,例如氮的杂原子可具有氢取代基和/或满足杂原子的化合价并且导致形成稳定部分的如本文所述的任何合适的取代基。
化合物可含有一个或多个不对称中心,因此以外消旋体和外消旋混合物、单一对映异构体、个体非对映异构体和非对映异构体混合物存在。本文明确包括这些化合物的所有这些异构形式。化合物也可以以多种互变异构形式表示,在这种情况下,本文明确地包括本文所述的化合物的所用互变异构形式,例如,环体系的烷基化可导致多个位点的烷基化,本文明确地包括所有这样的反应产物。本文明确地包括了这种化合物的所有这些异构形式。本文明确包括在此描述的化合物的所有晶体形式。
本发明化合物能够作为立体异构体或立体异构体的混合物存在;例如,构成它们的氨基酸能够相互独立地具有构型L-、D-或外消旋。因此,可能的是,获得异构混合物以及外消旋混合物或非对映体的混合物,或纯的非对映体或对映体,取决于不对称碳的数目和异构体或异构混合物所存在的不对称碳。本发明化合物的优选结构纯异构体,也即对映体或非对映体。
例如,在描述A3是-Phe-的情况下,应理解A3选自-L-Phe-,-D-Phe-或两者的混合物,是外消旋或非外消旋的。描述于该文献的制备程序使得本领域技术人员可以通过选择正确构型的氨基酸获得本发明化合物各自的立体异构体。
本发明的肽的药学上可接受的盐也属于本发明的领域之内。术语“药学上可接受的盐”意指其在动物中和更特别地在人类中的用途得到承认的盐,并且包括用以形成碱加成盐的盐,无论它们是无机盐还是有机盐,无机盐包括但不限于锂盐、钠盐、钾盐、钙盐、镁盐、锰盐、铜盐、锌盐或铝盐,或有机盐包括但不限于乙胺、二乙胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪;或者酸加成盐,无论它们是有机盐还是无机盐,有机盐包括但不限于乙酸盐、柠檬酸盐、乳酸盐、丙二酸盐、马来酸盐、酒石酸盐、富马酸盐、苯甲酸、天冬氨酸盐、谷氨酸盐、琥珀酸盐、油酸酯、三氟乙酸盐、草酸盐、双羟萘酸盐或葡糖酸盐,或无机盐包括但不限于盐酸盐、硫酸盐、磷酸盐、硼酸盐或碳酸盐。盐是化妆上或药学上可接受的,其性质不是关键。本发明肽的药学上可接受的盐能够通过现有技术中熟知的常规方法获得(Berge S.M.et al.,“Pharmaceutical Salts”,(1977),J.Pharm.Sci.,66,119,其通过引用整体并入本文)。
本发明提供了一种多肽化合物及其应用,多肽化合物或其立体异构体、药学上可接受的盐,具有式Ⅰ所示结构。实验结果表明,本发明提供的多肽化合物能够有效地对GHSR-1a表现出较高的激动活性,并且其结构新颖,毒副作用小,在血浆中具有较好的稳定性,具有成为临床候选化合物的潜力。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述。但本发明不限于以下实施例,基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。本发明所用未注明生产厂商的试剂或仪器,均为通过市购获得的常规产品。
实施例1~54:
化合物1~54的制备
多肽合成采用标准Fmoc固相方法,选用Rink Amide树脂,将C末端氨基酸与树脂结合,肽链由C端向N端延长。本发明采用的保护氨基酸包括:Fmoc-Apc(Boc)-OH,Fmoc-D-Lys(Boc)-OH,Fmoc-D-Orn(Boc)-OH,Fmoc-Phe-OH,Fmoc-D-Trp(Boc)-OH,Fmoc-D-Bal-OH,Fmoc-D-Cit-OH,Fmoc-D-Arg(Pbf)-OH,Boc-D-Aba-OH,Fmoc-Lys(Boc)-OH,Fmoc-Lys(Alloc)-OH,Fmoc-Gly-OH,Fmoc-D-Ala-OH,Fmoc-D-Val-OH,Fmoc-D-Leu-OH,Fmoc-Pro-OH,Fmoc-β-Ala-OH,Fmoc-D-Tle-OH,Fmoc-Tle-OH,Fmoc-D-Nle-OH,Fmoc-Nle-OH,顺-2-(叔丁氧羰酰胺)-1-环戊烷羧酸,Boc-甲基-1-(氨基甲基)环丁烷羧酸,1-N-Boc-3-吖丁啶羧酸,Boc-3-氨基氧杂环丁烷-3-甲酸,1-Boc-D-吖啶-2-羧酸,(S)-1-Boc-吡咯烷-3-甲酸,Boc-2-吗啉甲酸,(Boc-3-氨基-1-金刚烷)乙酸,(1R,3S,4S)-N-Boc-2-氮杂双环[2.2.1]庚烷-3-羧酸,3-Boc-3-氮杂双环[3.1.0]己烷-1-羧酸。缩合剂为HBTU/HOBt/DIEA。采用的脱保护试剂为哌啶/DMF溶液,采用水溶解粗肽后冻干保存。
采用中压液相色谱法或高效液相色谱法(HPLC)分离纯化多肽,多肽纯度大于90%,采用基质辅助激光解析飞行时间质谱(MALDI-TOF-MS)确定肽序列分子量。
肽序列的合成条件如下:
保护氨基酸(天然或非天然):0.2M的DMF溶液;
缩合剂:0.45M HBTU/HOBt的DMF溶液;
活化碱:2M DIEA的DMF溶液;
脱保护试剂:20%v/v哌啶的DMF溶液。
脱保护:称取0.23g(0.1mmoL)Rink Amide树脂置于多肽合成反应器中,将配置得到的脱保护试剂加入到树脂中,室温条件下进行反应,抽干,再次加入哌啶/DMF,室温条件下反应后抽干,并用DMF洗涤,直至检测合格。
缩合反应:在冰浴条件下分别将氨基酸、缩合剂加入DMF活化后,加入活化碱反应获得活化液,最后将活化液加入树脂中,室温条件下反应后,用5%茚三酮显色试剂使树脂显色,树脂变色后,抽干溶剂并采用DMF洗涤,检测合格后抽干溶剂,此时缩合反应完全。
重复上述脱保护和缩合反应直到肽链合成结束,得到包含完整多肽序列结构的肽树脂。
肽树脂的裂解:称取1.25g合成好的肽树脂,放入250mL茄形瓶中,冰浴,进行电磁搅拌。按1g肽树脂加入10mL的量配制裂解液【裂解液(v/v/v)为三氟乙酸:苯甲硫醚:水=90:5:5】。三氟乙酸(TFA)需预先冰浴降温30min或者预先存放于冰箱中使用;将配好的裂解液加入到冰浴条件下的肽树脂中,进行电磁搅拌,树脂变成黑色,冰浴条件下反应30min,然后撤掉冰浴,室温下继续搅拌反应180min,反应完成,剧烈搅拌下加入200mL冰乙醚,析出白色晶体,继续搅拌30min;用G4砂芯漏斗滤出析出物,采用冷乙醚洗涤析出物3次,晾干。采用50mL双蒸水和5mL乙腈充分溶解析出物,抽滤,将滤液冻干得到1.2g粗肽。
粗肽的纯化:采用中压或高效液相色谱纯化粗肽,色谱柱为C18柱,洗脱剂为乙腈,水和少量乙酸。纯化过程具体为:称取1.00g粗肽,加入20mL水和5mL乙腈溶解粗肽,离心10min(转速为5000r/min),取上清液。预先采用15%乙腈/水/0.1%冰乙酸溶液(200mL)平衡色谱柱。上样后继续采用15%乙腈/水/0.1%冰乙酸溶液(200mL)冲洗,高效液相检测洗脱液成分。根据液相检测结果逐渐升高乙腈含量,直至所纯化的多肽主峰被洗脱出来。合并洗脱液,旋转蒸发取出大部分溶剂,将纯的多肽进行冻干,HPLC检测含量大于90%,采用MALDI-TOF-MS确证分子量。
制备得到多肽化合物1~55,如下表1所示,表1为合成多肽化合物列表,采用本方法制备得到的54个多肽化合物,纯度为93.46%~99.48%。
表1合成多肽化合物列表
实施例55:
多肽化合物对GHSR-1a的激动活性评价实验(EC50)
GHSR活性化合物的筛选是通过重组表达受体来完成的。利用重组表达GHSR提供了几种优点,例如能够在确定的细胞系统中表达受体从而能够更容易区分化合物对GHSR的反应与对其它受体的反应。例如,可利用通常不用表达载体表达GHSR的诸如HEK293、COS7、以及CHO等细胞系中表达GHSR,而利用没有表达载体的相同细胞系作为对照。
可利用不同的技术来测量GHSR-1a的活性,例如,可通过检测GHSR-1a细胞内构象的变化、G-蛋白偶联活性的变化、和/或细胞内信使的变化等来进行测量。优选采用诸如测定细胞内Ca2+的技术来测量GHSR-1a活性。本领域公知的可用于测量Ca2+的技术的例子包括使用钙离子检测试剂盒等。钙离子检测试剂盒采用了钙离子敏感的指示剂以及屏蔽染料以确保研究者进行高灵敏的用于G蛋白偶联受体、离子通道和其它钙离子敏感的靶标的荧光筛选。本实验采用FLIPR钙6检测试剂盒和FLIPR钙6-QF检测试剂盒。
1.试验过程
1.1细胞培养及试剂配制
细胞系:Flp In-CHO-GHSR Stable Pool;
完全培养基:F12K+10%胎牛血清+1x盘尼西林-链霉素(PS)+600μg/mL潮霉素B;
细胞播种培养基:F12K+10%胎牛血清。
检测缓冲液:1X HBSS+20mM HEPES。
10X A组分:取试验缓冲液和A组分(供试品)至室温(RT),加10mL缓冲液于A组分中,涡旋1-2min,保存于-20℃;
1.2化合物管理
a)化合物库存溶液:按照标准协议,将实施例1~44制备得到的化合物1~44和对照样品ghrelin的粉末制成10mM DMSO溶液库存。
b)化合物存储:将DMSO中的所有化合物均存放在室温干燥器中进行短期存储(最多4个月)。剩余的化合物在-20℃下长期保存。
1.3激动剂活性试验
a)用完整培养基培养Flp In-CHO-GHSR Stable Pool细胞。
b)将7K细胞/孔置于384孔细胞培养板(Corning,3764)的25磅/英寸细胞播种培养基中,37℃,5%CO2培养过夜。
c)在室温条件下解冻10X A组分,用试验缓冲液将A组分稀释至2X,置于RT条件下。
d)从培养箱中取出培养皿,室温下平衡10min。将培养基改为检测缓冲液,最后洗涤后各孔保留缓冲液20μL,然后各孔加入2X A组分20μL,于37℃孵育3~5s。
e)在384孔细胞培养板上添加5X化合物10μL,采用FLIPR Tetra立即采集数据。
1.4数据分析
1)Z’factor=1-3*(SDMax+SDMin)/(MeanMax-MeanMin);
2)CVMax=(SDMax/MeanMax)*100%;
3)CVMin=(SDMin/MeanMin)*100%;
4)S/B=Singal/Background;
5)EC50值的计算公式:
Y=Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))
X:log value of compound concentration;Y:Activation%or Inhibition%
根据上述方法,活性测试结果如表2所示,表2为多肽化合物对GHSR-1a的活性(EC50),结果表明,本发明制备得到的多肽化合物1~44对GHSR-1a具有激动活性,大部分多肽化合物对GHSR-1a的激动活性高于对照ghrelin。
表2多肽化合物对GHSR-1a的活性(EC50)
实施例56:
多肽化合物对细胞色素P450氧化酶(CYP450)的抑制
药物的体内代谢过程可分为I相反应(分解代谢)和II相反应(合成代谢)。I相反应包括氧化、还原和水解反应,主要由细胞色素P450(CYP450)酶催化。CYP450酶主要分布在肝脏,故又称作肝药酶。CYP450酶的诱导和抑制具有重要的临床意义,可导致临床上的药物相互作用。因此,对CYP450的抑制实验常作为评价药物成药性的安全性指标。
以实施例1~44得到的化合物1~44作为测试化合物,将含有细胞色素P450的人肝微粒体(0.253mg/mL蛋白)与测试化合物(0.05~50μM)、CYPs底物(10μM对乙酰氨基酚、5μM双氯芬酸、30μM美芬妥因、5μM氢溴酸右美沙芬和2μM米达唑仑)和1.0mM NADP在37℃孵育10分钟。将萘黄酮、磺胺苯吡唑、N-3-苄基尼凡、奎尼定、酮康唑作为参比抑制剂。
结果如表3和表4所示,表3为化合物的细胞色素P450 CYP同工酶抑制活性(IC50),表4为参比抑制剂的细胞色素P450 CYP同工酶抑制活性,结果表明,本发明制备的大多数多肽化合物对细胞色素P450氧化酶的抑制活性低,IC50值均大于50μM。因此,此类化合物有望在体内不产生CYP抑制引起的各种毒性。
表3化合物的细胞色素P450 CYP同工酶抑制活性(IC50)
表4参比抑制剂的细胞色素P450 CYP同工酶抑制活性
实施例57:
hERG抑制实验
在心肌细胞中,hERG基因编码钾通道蛋白(Kv 11.1),该蛋白介导一种延迟整流钾电流(IKr)。抑制hERG会诱发获得性QT间期延长综合征(LQTS),导致炎症的心律失常。目前,检测化合物对hERG钾通道的作用已经成为临床前评价化合物心脏安全性的关键步骤,也是美国FDA和欧洲EMEA等管理机构要求的新药批报必备资料,以此规避心脏毒性风险。将一定浓度的待测化合物暴露于稳定表达hERG的HEK 293细胞,通过测定化合物对细胞在一定电压下的电流影响来确定化合物对hERG的抑制作用。
实验过程具体为:
A.细胞培养:将稳定表达hERG的HEK293细胞用DMEM培养基(10%FBS,0.1mM NEAA,25mM HEPES,100U/mL Penicillin-Streptomycin,5μg/mL Blasticidin and 400μg/mLGeneticin)培养。试验前,将细胞按照5×105个/皿的浓度接种到6cm的细胞培养皿中,并用含有脱氧土霉素的培养基培养48小时。
B.药物配置:将实施例1~35制备得到的化合物1~35分别溶解于DMSO中,制成浓度为10mM的化合物1~35溶液,分别将化合物1~35溶液与DMSO按1:3的比例梯度稀释为10、3.33、1.11和0.37mM的化合物1~35溶液,测试前采用buffer稀释为30、10、3.33、1.11和0.37μM,作为工作液。以化合物Dofetilide为阳性对照,其工作液的浓度为150、50、16.67、5.56和1.85nM。
C.测试:将培养皿放于显微镜的载物台上,在10x物镜下选择合适的细胞,并将电极对准细胞,转换到40x物镜后利用机械手的精细控制将电极靠近细胞表面。通过电极座的侧孔施加温和的吸力,形成一个千兆欧姆的密封。使用Cfast去除与阶跃电压相一致的电容电流,施加重复、短暂、强力的吸力,直到膜片破裂,获得完整的单个细胞的结构。此时将膜电位设置为-60mV,以确保不打开hERG通道。然后应该使用放大器上的Cslow来消除电容电流的峰值。设置保持电压为-90mV,持续500ms;记录在20khz和过滤器在10khz的电流,测试在-80mV、500ms的泄漏电流。在+30mV处去极化4.8s,然后将电压恢复到-50mV,持续5.2s,消除失活,观察失活尾流。用最大尾流大小确定hERG电流幅值。记录120s的电流以评估电流稳定性,只有记录参数高于阈值的稳定细胞才能继续给药。对细胞进行载体控制,建立基线。一旦发现hERG电流稳定了5分钟,就使用工作溶液,在测试化合物存在下记录大约5分钟的hERG电流以达到稳定状态,然后捕获5次扫描,在剂量反应试验中,从低浓度到高浓度,将5个剂量的试验化合物累积应用于细胞。为了保证培养细胞的良好性能和操作性,阳性对照组Dofetilide采用5个剂量对同一批细胞进行检测。
D.数据分析:
电流抑制率的计算公式如下:
采用Graphpad Prism 8.0绘制以抑制率为测试化合物剂量的响应曲线,并将数据拟合成具有可变斜率的s型剂量响应曲线。
实验结果如表5所示,表5为化合物的hERG抑制活性(IC50),结果表明,本发明制备的大多数化合物对hERG抑制IC50值均大于30μM,无明显抑制活性,心脏毒性风险低。
表5化合物的hERG抑制活性(IC50)
实施例58:
血浆稳定性实验
血浆中含有多种水解酶,具有某些官能团的化合物可以在血液中分解。不稳定化合物常具有较高的清除率和较短的半衰期,导致体内药代动力学(PK)差,药理学性能差。通过将一定浓度的待测化合物与不同种属动物的血浆孵育,测试孵育前后血浆中化合物的量,计算化合物的剩余百分比,确定化合物的稳定性。
实验过程:
A.孵育:用DMSO制备浓度为1mM的化合物1~35及阳性对照(Propanthelinebromide),再采用MeOH/H2O稀释到100μM,取2μL浓度为100μM的化合物1~35及阳性对照加入到98μL血清中,37℃水浴,于0、10、30、60、120分钟取样检测。
B.检测:向100μL孵育的样品中加入400μL终止液(200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的50%乙腈/甲醇溶液),混合均匀后,以4,000rpm/min离心10分钟。取50μL上清液与100μL超纯水混合后,以800rpm/min离心10分钟,然后采用LC-MS/MS检测化合物含量。
C.数据数据处理:按照下面公式计算化合物的剩余百分比:
化合物的剩余百分比(%)=100*(指定孵化时间120min的PAR/在T0时间的PAR);
其中,PAR为检测样品的峰面积。
实验结果如表6所示,表6为化合物的血浆稳定性,结果表明,本发明制备的化合物的血浆稳定性在不同种属中均表现良好,具有较好的成药潜力。
表6化合物的血浆稳定性
实施例59:
化合物55~60的制备以及活性检测
采用上述实施例1中所述相同的方法制备下表7所示的化合物55~60,根据实施例55所述的方法测试化合物55~60对GHSR-1a的活性(IC50)。
实验结果如表7所示,表7为多肽化合物对GHSR-1a的活性(IC50),结果表明,在实施例1~54的五肽化合物的C端添加额外的氨基酸不会显著影响其GHSR-1a激动活性。
表7多肽化合物对GHSR-1a的活性(IC50)
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (10)
1.多肽化合物或其立体异构体、药学上可接受的盐,具有式I所示结构:
U1-A1-A2-A3-U2-W-R1 式I;
其中,R1为-NR2R3,-OR2或-SR2;
并且,R1不为D型或L型氨基酸残基;
R2和R3相互独立地为氢、氘、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基;
W为单键、D型氨基酸残基或L型氨基酸残基;
U1选自以下任意一种结构:
其中,X和Z相互独立地选自以下任意一种结构:
其中R4和R12相互独立地为氢、氘、氨基、保护性基团基、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基或R5CO-;
R5为氢、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基;
Y和R11相互独立地为氢、氨基、硝基、羟基、卤素、氰基、胺甲基、胺乙基、胺丙基或胺丁基;
m1、m2、m3和m4相互独立地为0,1,2或3;
n1、n2、n3和n4相互独立地为0,1,2或3;
U2为以下结构,且U2的羰基端与W连接:
其中,R6为氢、氘、保护性基团、衍生自聚乙二醇的聚合物、非环状取代的或未经取代的脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基;
R7选自以下任意一种结构:
其中R8和R13相互独立地为氢、氘、氨基、保护性基团、衍生自聚乙二醇的聚合物、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基或R9CO-;
R9为氢、取代的或未经取代的非环状脂族基团、取代的或未经取代的脂环基、取代的或未经取代的杂环基、取代的或未经取代的杂芳基烷基、取代的或未经取代的芳基、取代的或未经取代的芳烷基;
p和q相互独立地为0、1、2、3、4或5;
A1为D型或L型氨基酸残基,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、鸟氨酸、3-(2-吡啶基)-丙氨酸、3-(3-吡啶基)-丙氨酸、3-(4-吡啶基)-丙氨酸、苯丙氨酸、4,4'-联苯丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、2'-(4-苯基)-咪唑基、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸、3-(4-喹啉基)-丙氨酸、3-(4-噻唑基)-丙氨酸、3-(2-噻吩基)-丙氨酸、3-(3-噻吩基)-丙氨酸、3-(1H-吡咯并[2,3-b]吡啶-3-基)丙氨酸或O-苄基-苏氨酸;
A2为D型或L型氨基酸残基,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、鸟氨酸、3-(2-吡啶基)-丙氨酸、3-(3-吡啶基)-丙氨酸、3-(4-吡啶基)-丙氨酸、苯丙氨酸、4,4'-联苯丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、2'-(4-苯基)-咪唑基、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸、3-(4-喹啉基)-丙氨酸、3-(4-噻唑基)-丙氨酸、3-(2-噻吩基)-丙氨酸、3-(3-噻吩基)-丙氨酸、3-(1H-吡咯并[2,3-b]吡啶-3-基)丙氨酸或O-苄基-苏氨酸;
其中,A1为3-(3-苯并噻吩基)-丙氨酸残基,A2不为3-(3-吲哚基)丙氨酸残基;
A3为D型或L型氨基酸,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、鸟氨酸、3-(2-吡啶基)-丙氨酸、3-(3-吡啶基)-丙氨酸、3-(4-吡啶基)-丙氨酸、苯丙氨酸、4,4'-联苯丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、2'-(4-苯基)-咪唑基、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸、3-(4-喹啉基)-丙氨酸、3-(4-噻唑基)-丙氨酸、3-(2-噻吩基)-丙氨酸、3-(3-噻吩基)-丙氨酸、3-(1H-吡咯并[2,3-b]吡啶-3-基)丙氨酸或O-苄基-苏氨酸。
4.根据权利要求1所述多肽化合物或其立体异构体、药学上可接受的盐,其特征在于,所述R1为-NR2R3或-OR2,其中R2和R3相互独立地为氢、甲基、乙基、己基、十二烷基或十六烷基。
5.根据权利要求1所述多肽化合物或其立体异构体、药学上可接受的盐,其特征在于,所述W为单键、丙氨酸残基、精氨酸残基、天冬酰胺残基、半胱氨酸残基、谷氨酰胺残基、天冬氨酸残基、谷氨酸残基、甘氨酸残基、组氨酸残基、异亮氨酸残基、亮氨酸残基、赖氨酸残基、甲硫氨酸残基、苯丙氨酸残基、脯氨酸残基、丝氨酸残基、苏氨酸残基、色氨酸残基、酪氨酸残基或缬氨酸残基。
6.根据权利要求1所述的多肽化合物或其立体异构体、药学上可接受的盐,其特征在于,所述A1为D型或L型氨基酸残基,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸或3-(4-喹啉基)-丙氨酸;
A2为D型或L型氨基酸,所述D型或L型氨基酸为:3-(3-苯并噻吩基)-丙氨酸、3-(3-吲哚基)丙氨酸、3-(1-萘基)-丙氨酸、3-(2-萘基)-丙氨酸、3-(2-喹啉基)-丙氨酸、3-(3-喹啉基)-丙氨酸或3-(4-喹啉基)-丙氨酸;
A3为D型苯丙氨酸残基或L型苯丙氨酸残基。
8.一种组合物,包括:权利要求1~7任意一项所述的多肽化合物或其立体异构体、药学上可接受的盐中的一种或多种;可接受的辅料。
9.权利要求1~7任意一项所述多肽化合物或其立体异构体、药学上可接受的盐在制备生长激素促分泌素受体的激动剂中的应用,或在制备用于治疗、预防、减轻和/或诊断由生长激素促分泌素受体介导的紊乱所致相关疾病的药物中的应用,或在制备促进生长发育的保健品中的应用。
10.权利要求8所述组合物在制备生长激素促分泌素受体的激动剂中的应用,或在制备用于治疗、预防、减轻和/或诊断由生长激素促分泌素受体介导的紊乱所致相关疾病的药物中的应用,或在制备促进生长发育的保健品中的应用。
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