CN113045625B - 作为生长激素促分泌素受体激动剂的多肽及其应用 - Google Patents
作为生长激素促分泌素受体激动剂的多肽及其应用 Download PDFInfo
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Classifications
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- C07K7/02—Linear peptides containing at least one abnormal peptide link
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- 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
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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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
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明提供了一种作为生长激素促分泌素受体激动剂的多肽,具有式Ⅰ所示结构,或其立体异构体、混合物、药学上可接受的盐。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,具有成为临床候选化合物的潜力。
Description
技术领域
本发明涉及生物医药技术领域,尤其涉及一种作为生长激素促分泌素受体激动剂的多肽及其应用。
背景技术
生长激素是由脑垂体促生长激素细胞中释放的,可以刺激所有能够生长的组织生长,还对代谢过程具有一些作用并在能量代谢中引起从碳水化合物到脂肪酸代谢的交换。生长激素从促生长激素细胞中释放受到两种下丘脑神经肽的调控,分别是促进释放的生长激素释放激素和抑制释放的生长激素释放抑制激素。生长激素促分泌激素受体(GrowthHormone Secretagogue Receptor,GHSR),也被称为胃饥饿素受体,是由7个跨膜α螺旋组成的G蛋白偶联受体,多分布于垂体、胃部、肠等部位,同样调控促生长激素细胞中生长激素的释放。GHSR结构编码基因组在不同物种中高度保守,其氨基酸排列顺序与胃动素基因相关肽的G蛋白偶联蛋白受体有52%同源性。GHSR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)、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。
胃饥饿素(Ghrelin)是一种由28个氨基酸残基组成的脑肠肽,是GHSR-1a的内源性配体,最初是1999年由日本学者Kojima在大鼠胃黏膜中分离纯化而取得。Ghrelin通过与其受体GHSR-1a相结合而发挥多种生物学效应,包括促进生长激素分泌、增加食欲、抑制炎症因子释放等等。同时,生长激素的释放也可由生长激素释放肽(GHRP)控制,其结构为含有六个氨基酸残基的线性肽,序列为:H-His-D-Trp-Ala-Trp-D-Phe-Lys-CONH2(GHRP-6)。GHRP-6可以与GHSR相结合而产生激动活性,发挥生物学效应,在包含人在内的几种物种中以剂量依赖的方式从促生长激素细胞中释放生长激素(Bowers et.al.,Endocrinology 1984,114,1537-1545)。
通过对GHRP-6的结构进行分析,研究人员又发现了一些GHRP类似物,可以与GHSR-1a结合,产生激动活性,引起信号转导,从而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新颖分子结构是GHSR-1a受体激动剂的研究目标。
发明内容
有鉴于此,本发明要解决的技术问题在于提供一种作为生长激素促分泌素受体激动剂的多肽及其应用,作为GHSR-1a受体激动剂具有较高的活性。
为达到上述目的,本发明提供了一种作为生长激素促分泌素受体激动剂的多肽,具有式Ⅰ所示结构,或其立体异构体、混合物、药学上可接受的盐:
U1-A1-A2-A3-U2-W-R1 式Ⅰ;
其中,R1选自-NR2R3,-OR2或-SR2;
并且,R1不为D型或L型氨基酸;
R2和R3独立地选自氢,氘,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,取代的或未经取代的芳烷基;
W选自单键、D型氨基酸或L型氨基酸;
U1选自以下任一结构:
其中,X和Z独立地选自CH-R4,N-R4,O,S,Se,S=O或O=S=O;
R4,R7和R8独立地选自氢,氘,氨基、保护基,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,取代的或未经取代的芳烷基(优选取代或未经取代的芳基-C1-6烷基)或R9CO-;
R9选自氢,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,取代的或未经取代的芳烷基;
Y选自卤素、氨基、硝基、羟基或氰基;
R5选自-NR2R3,-OR2或-SR2;
R6选自氢,氘,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,取代的或未经取代的芳烷基;
m1、m2、m3、m4独立地选自0,1,2或3;
n1,n2,n3和n4独立地选自0,1,2或3;
p为0,1,2,3,4或5;
U2选自以下结构,且U2的羰基端与W连接:
其中,R10选自氢,氘,保护基,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;
t为0,1,2,3,4,5;
A1和A2独立地选自以下D型或L型氨基酸:3-(3-苯并噻吩基)-丙氨酸,4,4'-联苯丙氨酸,4-苯甲酰基-苯丙氨酸,3,3-二苯基丙氨酸,3-(1-萘基)-丙氨酸,3-(2-萘基)-丙氨酸,O-苄基-丝氨酸或色氨酸;
A3选自以下D型或L型氨基酸:3-(2-呋喃基)-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,2,3,4,5,6-五氟苯丙氨酸,苯丙氨酸,2'-(4-苯基)-咪唑基,3-(4-噻唑基)-丙氨酸,3-(2-噻吩基)-丙氨酸,3-(3-噻吩基)-丙氨酸或O-苄基-苏氨酸。
本发明中,所述R1选自-NR2R3,-OR2或SR2。
其中,R2和R3独立地选自氢,氘,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,取代的或未经取代的芳烷基。更优选为氢,氘,衍生自聚乙二醇的聚合物,非环状取代的或未经取代的C1-10脂族基团,取代的或未经取代的C3-10脂环基,取代的或未经取代的C2-10杂环基,取代的或未经取代的C2-20杂芳基烷基,取代的或未经取代的C6-12芳基或取代的或未经取代的C6-12芳烷基。
本发明优选的,所述R1选自-NR2R3或-OR2,其中R2和R3独立地选自氢,甲基,乙基,己基,十二烷基或十六烷基。
本发明中,所述R1不为D型或L型氨基酸。
本发明中,上述氨基酸指氨基酸残基,具体的,为氨基酸通过氨基或羧基反应,形成多肽后的残基。
本发明中,所述W独立地选自单键、D型氨基酸或L型氨基酸。更优选的,所述W选自单键、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,缬氨酸残基中的一种或多种。
本发明中,当所述W选自单键时,即U2和R1直接相连接。
当所述W选自D型氨基酸或L型氨基酸时,所述氨基酸脱去一分子水,和相邻基团形成酰胺键。
所述残基是指W通过脱去一分子水和相邻基团形成酰胺键,进而形成多肽化合物。
本发明中,所述U1选自以下任一结构:
其中,X和Z独立地选自CH-R4,N-R4,O,S,Se,S=O或O=S=O;更优选为N-R4或O。
R4,R7和R8独立地选自氢,氘,氨基、保护基,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,取代的或未经取代的芳烷基或R9CO-;更优选为氢,氘,氨基、衍生自聚乙二醇的聚合物,非环状取代的或未经取代的C1-10脂族基团,取代的或未经取代的C3-10脂环基,取代的或未经取代的C2-10杂环基,取代的或未经取代的C2-20杂芳基烷基,取代的或未经取代的C6-12芳基,取代的或未经取代的C6-12芳烷基或R9CO-。进一步优选为氢,氨基、C1-6烷基,C6-14芳基,C3-8环烷基或C2-10酰基。
所述R9优选为氢,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,取代的或未经取代的芳烷基;更优选为氢,非环状取代的或未经取代的C1-10脂族基团,取代的或未经取代的C3-10脂环基,取代的或未经取代的C2-10杂环基,取代的或未经取代的C2-20杂芳基烷基,取代的或未经取代的C6-12芳基,取代的或未经取代的C6-12芳烷基。进一步优选为氢或C1~6烷基;在本发明的一些具体实施例中,所述R9具体为甲基、乙基、丙基、异丙基或丁基。
本发明中,所述Y选自卤素、氨基、硝基、羟基或氰基。更优选为F、Cl、Br或氨基。
本发明中,所述R5独立地选自-NR2R3,-OR2或-SR2;更优选为-NR2R3。
上述R2、R3的范围同上,在此不再赘述。
进一步优选的,R2、R3独立的选自氢、甲基、乙基或己基。
本发明中,所述R6独立地选自氢,氘,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,取代的或未经取代的芳烷基;更优选为氢,氘,非环状取代的或未经取代的C1-10脂族基团,取代的或未经取代的C3-10脂环基,取代的或未经取代的C2-10杂环基,取代的或未经取代的C2-20杂芳基烷基,取代的或未经取代的C6-20芳基,取代的或未经取代的C6-12芳烷基。进一步优选为氢、C1-6烷基、C6-14芳基或C3-8环烷基。
本发明优选的,所述U1选自以下结构:
其中,R6选自氢,取代或非取代的C1-6烷基,取代或非取代的C6-14芳基,取代或非取代的C3-8环烷基;所述取代的基团优选为卤素、氨基、硝基、羟基、酰基取代的氨基、脲基或胍基。
进一步优选的,所述R6选自氢,取代或未取代的甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基。
所述取代的基团选自卤素、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。
R7和R8独立地优选为氢,C1-6烷基,C6-14芳基,C3-8环烷基,C2-10酰基;更优选为氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、甲酰基、乙酰基、丙酰基或丁酰基。
本发明优选的,所述U1选自以下任一结构:
其中,R11、R12独立地优选为氢、氨基、硝基、羟基、卤素、氰基、胺甲基、胺乙基、胺丙基或胺丁基。
本发明优选的,所述U2选自以下结构,且U2的羰基端与W连接:
其中,R10选自氢,氘,保护基,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。更优选为氢或C1~6烷基。
t优选为0,1,2,3,4,5;更优选为2或3。
本发明中,A1和A2独立地选自具有芳香结构侧链的氨基酸残基,优选选自以下D型或L型氨基酸:3-(3-苯并噻吩基)-丙氨酸(Bal),4,4'-联苯丙氨酸(Bip),4-苯甲酰基-苯丙氨酸(Bpa),3,3-二苯基丙氨酸(Dip),3-(1-萘基)-丙氨酸(lNal),3-(2-萘基)-丙氨酸(2Nal),O-苄基-丝氨酸【Ser(Bzl)】或色氨酸(Trp)。
A3独立地选自具有芳香结构侧链的氨基酸残基,优选选自以下D型或L型氨基酸:3-(2-呋喃基)-丙氨酸(2Fua),鸟氨酸(Orn),3-(2-吡啶基)-丙氨酸(2Pal),3-(3-吡啶基)-丙氨酸(3Pal),3-(4-吡啶基)-丙氨酸(4Pal),2,3,4,5,6-五氟苯丙氨酸(Pff),苯丙氨酸(Phe),2'-(4-苯基)-咪唑基(Pim),3-(4-噻唑基)-丙氨酸(Taz),3-(2-噻吩基)-丙氨酸(2Thi),3-(3-噻吩基)-丙氨酸(3Thi)或O-苄基-苏氨酸【Thr(Bzl)】。
在本发明的一些具体实施例中,A1选自以下D型氨基酸:3-(3-苯并噻吩基)-丙氨酸(Bal);A2选自以下D型氨基酸:色氨酸(Trp);A3选自以下L型氨基酸:苯丙氨酸(Phe);
在U2中,R10选自氢。
即本发明提供的作为生长激素促分泌素受体激动剂的多肽具有式Ⅰ-b所示结构通式:
U1-D-Bal-D-Trp-Phe-U2-W-R1 式Ⅰ-b;
或具有式Ⅱ所示结构:
本发明中,所述m1、m2、m3、m4独立地选自0,1,2或3;
本发明中,n1,n2,n3和n4独立地选自0,1,2或3。
本发明中,p为0,1,2,3,4或5。
本发明中,当p为0时,所述N原子直接和C原子相连接。
本发明优选的,所述作为生长激素促分泌素受体激动剂的多肽,具有以下任一结构,或其立体异构体、混合物、药学上可接受的盐:
在本发明的实施方案中,如本文所述的作为生长激素促分泌素受体激动剂的多肽、它们的立体异构体、其混合物、它们的药学上可接受的盐的合成能够根据现有技术已知的任何常规方法进行,比如用固相肽合成方法[Stewart J.M.y Young J.D.,“Solid PhasePeptide Synthesis,2nd edition”,(1984),Pierce Chemical Company,Rockford,Illinois;Bodanzsky M.y Bodanzsky A.,“The practice of Peptide Synthesis”,(1994),Springer Verlag,Berlin;Lloyd Williams P.et al.,“Chemical Approaches tothe Synthesis of Peptides and Proteins”,(1997),CRC,Boca Raton,FL,USA],溶液中的合成、酶促合成[Kullmann W.“Proteases as catalysts for enzymic syntheses ofopioid peptides”,(1980),J.Biol.Chem.,255(17),8234-8238]或其任意组合。化合物还能够通过经过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,或者通过动物、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。例如,可以使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产生本发明的化合物。
仅作为示例,获得本发明的多肽化合物、它们的立体异构体和其混合物的方法可以包括下述阶段:
-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;
-消除保护N-末端的基团;
-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;
-消除保护C-末端的基团或裂解固体载体;
优选地,C-末端结合至固体载体并且该过程在固相中进行,因此包括将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;和按必要次数重复该程序以获得所希望长度的化合物,最终随后从最初的聚合物载体的裂解合成的化合物。
在整个合成当中,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,固相合成能够用会聚策略进行: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。
在采用现有技术已知的标准程序和条件的情况下,本发明过程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,R1残基能够这样引入: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/裂解步骤和它们随后的衍生化能够根据现有技术已知的过程以不同顺序进行。
本发明提供了一种组合物,包括作为生长激素促分泌素受体激动剂的多肽,和可接受的辅剂。
本发明中,上述组合物可以为药物组合物,或保健品组合物。
本发明中,所述辅剂包括但不限于本领域技术人员熟知的载体、稀释剂、赋形剂或辅助剂等。
本发明优选的,所述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)、具有HEPES的MEM,等等。
本发明上述组合物中,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,并适合治疗、预防、减轻或诊断由GHSR-1a介导的紊乱所致相关疾病。
基于此,本发明提供了上述多肽化合物,或上述制备方法制备的多肽化合物,或上述组合物,作为生长激素促分泌素受体的激动剂的应用,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,或作为促进生长发育的保健品中的应用。
本发明中,所述生长激素促分泌素受体,也可以称之为胃饥饿素受体、生长激素释放肽受体或GHSR-1a受体。
本发明优选的,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。
具体的,本发明提供了上述多肽化合物,或上述制备方法制备的多肽化合物,或上述组合物作为GHSR-1a激动剂的用途。
具体的,本发明提供了上述多肽化合物,或上述制备方法制备的多肽化合物,或上述组合物在制备GHSR-1a激动剂的用途。
本发明提供的上述多肽化合物、组合物,或生长激素促分泌素受体的激动剂可以以多种方式施用,这取决于期望局部施用还是全身性施用并取决于待治疗的区域。在一些实施方案中,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。保护性基团、它们的相对反应性和它们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尤其是酰胺乙酸酯,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。
三官能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。
在优选实施方式中,所用的保护性基团策略是如下的策略: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保护并且Apc赖氨酸和鸟氨酸侧链通过CIZ、Fmoc或Alloc保护。
在又一优选的实施方式中,所用的保护性基团策略是如下的策略: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,并且赖氨酸和鸟氨酸侧链通过Boc、Trt或Alloc保护。
这些和其它保护性基团的实例,它们的引入和除去,能够参考文献[AthertonB.and Sheppard R.C.,“Solid Phase Peptide Synthesis:A practical approach”,(1989),IRL Oxford University Press]。术语“保护性基团”也包括固相合成中的聚合物载体。
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可能固体载体涉及聚苯乙烯载体,接枝至聚苯乙烯的聚乙二醇等,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)等,其可以包括或可以不包括不稳定连接体,比如5-(4-氨甲基-3,5-二甲氧基苯氧基)戊酸(PAL)[Albericio F.et al.,“Preparation and application of the 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)valeric acid(PAL)handle for the solid-phasesynthesis of C-terminal peptide amides under mild conditions”,(1990),J.Org.Chem.,55,3730-3743],2-[4-氨甲基-(2,4-二甲氧基苯基)]苯氧基乙酸(AM)[RinkH.,“Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methylester resin”,(1987),Tetrahedron Lett.,28,3787-3790],Wang[WangS.S.,“p-Alkoxybenzyl Alcohol Resin and p-Alkoxybenzyl oxycarbonylhydrazideResin for Solid Phase Synthesis of Protected Peptide Fragments”,(1973),J.Am.Chem.Soc.,95,1328-1333]等,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-和L-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。
“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)和(D)形式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)。
如本文所用,术语“非环状脂族基团”涵盖线性或支化的烷基,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,包括例如且不限于,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,5-甲基己基等。
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,包括例如且不限于乙烯基(-CH2=CH2),烯丙基(-CH2-CH=CH2),油烯基,亚油烯基等基团。
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,包括例如且不限于乙炔基基团,1-丙炔基,2-丙炔基,1-丁基,2-丁基,3-丁基,戊基,比如1-戊基等。炔基基团还能够含有一个或多个碳-碳双键,包括例如且不限于基团丁-1-烯-3-炔基,戊-4-烯-1-炔基等。
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,包括例如且不限于,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,十二氢非那烯等。
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,包括例如且不限于环戊-1-烯-1-基基团等。
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,包括例如且不限于环辛-2-炔-1-基基团等。环炔基基团还能够含有一个或多个碳-碳双键,包括例如且不限于环辛-4-烯-2-炔基基团等。
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,包括例如且不限于苯基,萘基,二苯基,茚基,菲基或蒽基等;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。出于本发明意图,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。术语杂环基最优选是指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、-(CH2)1-6-吡咯烷基等。
本文使用的术语“卤素”或变体如“卤化物”或“卤代”是指氟,氯,溴和碘。
如本文所用的术语“杂原子”或变体如“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,叔丁氧基等。
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能够是-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,无机盐比如且不限于锂、钠、钾、钙、镁、锰、铜、锌或铝等,或有机盐比如且不限于乙胺、二乙胺、乙醇胺、二乙醇胺、精氨酸、赖氨酸、组氨酸或哌嗪等;或者酸加成盐,无论它们是有机盐还是无机盐,有机盐比如且不限于乙酸盐,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等,或无机盐比如且不限于盐酸盐,硫酸盐,磷酸盐,硼酸盐或碳酸盐等。盐的性质不是关键,条件是它是化妆上或药学上可接受的。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(BergeS.M.等人,“Pharmaceutical Salts”,(1977),J.Pharm.Sci.,66,119,其通过引用整体并入本文)。
与现有技术相比,本发明提供了一种作为生长激素促分泌素受体激动剂的多肽,具有式Ⅰ所示结构,或其立体异构体、混合物、药学上可接受的盐。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,具有成为临床候选化合物的潜力。
具体实施方式
为了进一步说明本发明,下面结合实施例对本发明提供的作为生长激素促分泌素受体激动剂的多肽及其应用进行详细描述。
本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。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。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
多肽合成采用标准的Fmoc固相方法。选用Rink Amide树脂,肽链由C端向N端延长。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。脱保护试剂为哌啶/DMF溶液。粗肽水溶解后冻干保存。用中压液相色谱法或高效液相色谱法(HPLC)分离纯化,纯肽含量大于90%。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:
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。
实施例1-43:化合物1-43的制备
1.脱保护:称取Rink Amide树脂0.23g(0.1mmol)置于多肽合成反应器中,然后将脱保护试剂按上述浓度配置好后,加入到树脂中,室温条件下反应,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。
2.缩合反应:在冰浴条件下分别将氨基酸,缩合剂加入DMF活化,再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%的茚三酮显色试剂使树脂显色,树脂变色,抽干溶剂并用DMF洗涤,检测合格后抽干溶剂,此时缩合反应完全。
3.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。
4.肽树脂的裂解:称取合成好的肽树脂1.25g,放入250ml茄形瓶中,冰浴,电磁搅拌。按1g肽树脂加入10ml的量配制裂解液【裂解液(体积百分比):三氟乙酸:苯甲硫醚:水=90:5:5】。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,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,剧烈搅拌下加入冰乙醚200ml,析出白色晶体,继续搅拌30min;用G4砂芯漏斗滤出析出物,用冷乙醚反复洗涤3遍,晾干。加入双蒸水50ml,乙腈5ml使固体充分溶解,抽滤,滤液冻干得粗肽1.2g。
5.粗肽的纯化:粗肽用中压或高效液相色谱进行纯化。色谱柱为C18柱,洗脱剂为乙腈,水和少量乙酸。具体操作步骤:称取粗肽1.00g,加水20ml,乙腈5ml使固体溶解,离心10min(5000转/分钟),取上清液上样。色谱柱预先用15%乙腈/水/0.1%冰乙酸溶液200ml平衡。上样后继续用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,冻干纯的多肽,HPLC检测含量大于90%,MALDI-TOF-MS确证分子量。
制备的多肽化合物如下表1所示。
表1合成多肽化合物列表
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实施例44:多肽化合物对GHSR-1a的激动活性评价实验(IC50)
GHSR-1a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-1a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-1a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-1a的诸如HEK293、COS7、以及CHO等细胞系中表达GHSR-1a,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
a)细胞系:Flp In-CHO-GHSR Stable Pool;
b)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;
c)细胞播种培养基:F12K+10%胎牛血清。
d)检测缓冲液:1X HBSS+20mM HEPES。
e)10X A组分:取试验缓冲液和A组分至室温(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,将来自内部合成的粉末制成10mM DMSO溶液库存。
b)化合物存储: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20X 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,室温平衡10min。将培养基改为杏色缓冲液,最后洗涤后各孔保留缓冲液20μl,然后各孔加入2XA组分20μl,37℃孵育3-5s。
e)在384孔细胞培养板上添加5X化合物10μl,用FLIPR Tetra立即采集数据。
2.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)IC50值的计算公式:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-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多肽化合物对GHSR-1a的活性(IC50)
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由表2的结果可知,本发明制备的多肽化合物显示出了对GHSR-1a的激动活性。
实施例45: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)及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。
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、2μM米达唑仑)、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、酮康唑作作为参比抑制剂。结果如表3所示。
表3化合物的细胞色素P450 CYP同工酶抑制活性(IC50)
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由表3的结果可知,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IC50值均大于50μM。
实施例46:多肽化合物44-47的制备以及活性检测
采用上述实施例1-43中所述相同的方法制备下表4所示的化合物44-47,并根据实施例44所述的方法测试这些化合物对GHSR-1a的活性(IC50),结果如表4所示。
表4多肽化合物对GHSR-1a的活性(IC50)
从表4的结果可知,在实施例1-43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。
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 (3)
1.一种作为生长激素促分泌素受体激动剂的多肽,为以下任一结构,或其立体异构体、药学上可接受的盐:
2.一种组合物,包括权利要求1所述的作为生长激素促分泌素受体激动剂的多肽,和可接受的辅剂。
3.权利要求1所述的作为生长激素促分泌素受体激动剂的多肽,或权利要求2所述的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,所述相关疾病为生长激素缺乏症。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014415A1 (en) * | 2002-08-09 | 2004-02-19 | Societe De Conseil De Recherches Et D'applications Scientifiques, S.A.S. | Growth hormone releasing peptides |
WO2009020643A2 (en) * | 2007-08-08 | 2009-02-12 | Ipsen Pharma S.A.S. | Method for inhibiting inflammation and pre-inflammatory cytokine/chemokine expression using a ghrelin analogue |
WO2011115871A1 (en) * | 2010-03-15 | 2011-09-22 | Ipsen Pharma S.A.S. | Pharmaceutical compositions of growth hormone secretagogue receptor ligands |
CN106459149A (zh) * | 2014-03-04 | 2017-02-22 | 莫图斯治疗公司 | H‑inp‑(d)bal‑(d)trp‑phe‑apc‑nh2及其可药用盐的液相合成的方法 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014415A1 (en) * | 2002-08-09 | 2004-02-19 | Societe De Conseil De Recherches Et D'applications Scientifiques, S.A.S. | Growth hormone releasing peptides |
WO2009020643A2 (en) * | 2007-08-08 | 2009-02-12 | Ipsen Pharma S.A.S. | Method for inhibiting inflammation and pre-inflammatory cytokine/chemokine expression using a ghrelin analogue |
WO2011115871A1 (en) * | 2010-03-15 | 2011-09-22 | Ipsen Pharma S.A.S. | Pharmaceutical compositions of growth hormone secretagogue receptor ligands |
CN106459149A (zh) * | 2014-03-04 | 2017-02-22 | 莫图斯治疗公司 | H‑inp‑(d)bal‑(d)trp‑phe‑apc‑nh2及其可药用盐的液相合成的方法 |
Non-Patent Citations (2)
Title |
---|
GHS-1a Agonists That Effectively Stimulate Food Intake and Body Weight Gain;Jesse Z. Dong等;《Peptides for Youth》;20091231;第1085-1088页 * |
生长激素释放肽(ghrelin)促生长作用和应用前景;来景辉等;《动物营养学报》;20110715(第07期);第1085-1088页 * |
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