CN113072617A - 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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- CN113072617A CN113072617A CN202110343062.2A CN202110343062A CN113072617A CN 113072617 A CN113072617 A CN 113072617A CN 202110343062 A CN202110343062 A CN 202110343062A CN 113072617 A CN113072617 A CN 113072617A
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- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 1
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- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
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- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
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- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
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- 125000005500 uronium group Chemical group 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
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Abstract
本发明提供了一种多肽化合物,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。
Description
技术领域
本发明涉及生物医药技术领域,尤其涉及一种多肽化合物及其应用。
背景技术
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。ghrelin是Kojima等在小鼠和人胃内分泌细胞及下丘脑弓状核中发现的,是目前为止发现的唯一的GHSR天然配体,它含有28个氨基酸残基,分子量为3.3kDa。人和大鼠的ghrelin前体蛋白由117个氨基酸组成,N端前23肽呈现分泌信号肽的特征;ghrelin的N端前4个氨基酸片段为其最小的活性中心,C末端的P-R结构(脯氨酸-精氨酸)为其识别部位。人和大鼠的ghrelin只有2个氨基酸残基不同,编码基因序列有82.9%的同源性。ghrelin在体内有两种分泌形式:一种是ghrelin的N端第3位丝氨酸发生了辛酰基化,另一种是该部位没有发生辛酰基化。ghrelin的N端第3位丝氨酸是其发挥生物学功能的实质部位。最初的研究认为去辛酰基化ghrelin(des-acylghrelin)不具备生物学活性,而最新研究发现,去辛酰基化和辛酰基化的ghrelin均能够促进脊索神经上皮的增殖;去辛酰基化ghrelin具有内分泌功能,能促进细胞增殖,具有抗凋亡作用。
GHSR是一种孤核的G蛋白耦联受体,除主要存在于啮齿动物和人的垂体、胃部外,还广泛分布于外周组织、脑、肠、肾脏、胰脏、心脏、脂肪组织等。GHSR分布的广泛性对ghrelin及其受体的多种生物学功能起重要作用。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。
生长激素(growth hormone,GH)在垂体的脉冲式释放主要受下丘脑的生长激素释放激素(growth hormone releasing hormone,GHRH)、生长抑素(Somatostatin,SS)和ghrelin三个因子调节。对GH的分泌,GHRH起促进作用,SS起抑制作用,ghrelin可与GHRH协同起到促进作用,三者在下丘脑形成局部神经内分泌调节反馈环。在调节GH分泌的系统中,GHRH与其受体结合,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。GH从垂体促生长激素细胞的释放也可受到生长激素释放多肽(GHRP)的控制。已经发现有一种六肽,H-His-D-Trp-Ala-Trp-D-Phe-Lys-CONH2(GHRP-6)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)。通过对GHRP-6的结构进行分析,研究人员又发现了一些GHRP类似物。
该类多肽以及类肽等化合物可以与GHSR-1a结合,产生激动活性,引起信号转导,从而调节GH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,改善多肽的稳定性,是行之有效的药物开发策略之一。
发明内容
有鉴于此,本发明要解决的技术问题在于提供一种多肽化合物及其应用,制备的多肽化合物作为GHSR-1a受体激动剂具有较高的活性。
为达到上述目的,本发明提供了一种多肽化合物,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:
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或R9CO-;
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和m2独立地选自0,1,2或3;特别地,当X为N时,m1为2,m2则独立地选自0,1,3;m2为2,m1则独立地选自0,1,3;
m3和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为单键,或选自以下任一结构,且U2的羰基端与W连接:
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。
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,R10、R11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为单键,或选自以下任一结构(即4-氨基-4-哌啶甲酸(Apc)或赖氨酸(Lys),鸟氨酸(Orn),精氨酸(Arg)残基),且U2的羰基端与W连接:
本发明中,当U2为单键时,W直接和母核的羰基相连接。
本发明中,所述m1和m2独立地选自0,1,2或3;特别地,当X为N时,m1为2,m2则独立地选自0,1,3;m2为2,m1则独立地选自0,1,3;即所述含m1和m2的结构不选自吡啶基团。
本发明中,m3和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,所述多肽化合物,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,如本文所述的多肽化合物、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 Phase Peptide Synthesis,2ndedition”,(1984),Pierce Chemical Company,Rockford,Illinois;Bodanzsky M.yBodanzsky A.,“The practice of Peptide Synthesis”,(1994),Springer Verlag,Berlin;Lloyd Williams P.et al.,“Chemical Approaches to the Synthesis ofPeptides 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 of opioidpeptides”,(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,包括上述多肽化合物,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.etal.,“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
Apc(4-Amino-4-piperidine formic acid)4-氨基-4-哌啶甲酸
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(3-Amino-4-phenylbutyric acid,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U2能够是-Lys-的情况下,应理解U2选自-L-Lys-,-D-Lys-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,本发明提供了一种多肽化合物,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。
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多肽化合物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
化合物1-5,9,11-35,39,41-80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1.04g。
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。
实施例2
化合物10,40的制备:
本实施例基于实施例1,与实施例1的区别在于,肽链N端最后一个保护氨基酸为Fmoc-Lys(Alloc)-OH,其侧链保护基脱除方法为:抽干的树脂中加入三苯基膦钯:苯硅烷=1:10(v/v),避光,N2保护反应3h,经检测树脂变色,脱保护完全;将树脂洗净抽干之后,进行乙酰化反应:加入乙酸2ml,DIEA2ml,反应30min,洗净抽干。最后在20%v/v哌啶的DMF溶液中脱除Fmoc保护基,经裂解和纯化得到。
实施例3
化合物6-8,36-38的制备:
本实施例基于实施例1,与实施例1的区别在于,肽链N端最后一个氨基酸脱保护完成后,加入乙酸2ml,DIEA 2ml,反应30min,进行乙酰化封端,最后经裂解和纯化得到。
由本文所公开的实施方案的合成方法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
实施例4
多肽化合物对GHSR-1a的激动活性评价实验(IC50)
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)
由表2的结果可知,本发明提供的多肽化合物显示了对GHSR-1a的激动活性。
实施例5
多肽化合物对细胞色素P450氧化酶的抑制
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℃温育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)
由表3的结果可知,本发明提供的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6
多肽化合物81-84的制备以及活性检测
采用上述实施例1-80中所述相同的方法制备下表4所示的化合物81-84,并根据实施例4所述的方法测试这些化合物对GHSR的活性(IC50)结果如表4所示。
表4 多肽化合物对GHSR的活性(IC50)
从表4的结果可知,在化合物1-80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 (10)
1.一种多肽化合物,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:
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或R9CO-;
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和m2独立地选自0,1,2或3;特别地,当X为N时,m1为2,m2则独立地选自0,1,3;m2为2,m1则独立地选自0,1,3;
m3和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为单键,或选自以下任一结构,且U2的羰基端与W连接:
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。
2.根据权利要求1所述的多肽化合物,其特征在于,所述R7和R8选自氢,C1-6烷基,C6-14芳基,C3-8环烷基或C2-10酰基;
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。
3.根据权利要求1所述的多肽化合物,其特征在于,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。
5.根据权利要求4所述的多肽化合物,其特征在于,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独立地选自氢、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;
p为0,1,2,3,4或5。
8.一种组合物,包括权利要求1~7任一项所述的多肽化合物,和可接受的辅剂。
9.权利要求1~7任一项所述的多肽化合物,或权利要求8所述的组合物,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。
10.根据权利要求9所述的应用,其特征在于,所述相关疾病为生长激素缺乏症。
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