CN103314006B - 新型血管紧张素2型(at2)受体激动剂及其应用 - Google Patents
新型血管紧张素2型(at2)受体激动剂及其应用 Download PDFInfo
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Abstract
本发明涉及一种新型药学有用的肽,具体是环肽,该环肽是血管紧张素II-2型受体(AT2受体)的激动剂。本发明进一步涉及这种肽作为药物的应用、含有这种肽的药物组合物以及它们的制造。
Description
技术领域
本发明涉及一种新型药学有用的肽,具体是环肽,该环肽是血管紧张素II-2型受体(下文的AT2受体)的激动剂。本发明进一步涉及这种肽作为药物的应用、含有这种肽的药物组合物以及它们的制造的合成路径。
背景技术
内源性激素AngII是线性八肽(Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8),并且是肾素-血管紧张素***(RAS)的活性成分。通过肾素和血管紧张素转化酶(ACE)的激素原血管紧张素原的顺序加工来产生内源性激素AngII。RAS在血压、体液和电解质平衡的调控中起着重要作用。AngII在许多器官中发挥这些生理作用,这些器官包括:肾脏、肾上腺、心脏、血管、脑、消化道和生殖器官(deGasparo等,Pharmacol.Rev.(2000)52,415-472)。已经识别了AngII受体的两个主要类别,且这两个主要类别被指定为1型受体(下文的AT1受体)和AT2受体。AT1受体在大多数的器官中表达,并且被认为是造成AT2的多数生物学影响的原因。在胎儿组织、成人卵巢、肾上腺和胰腺中,AT2受体比AT1受体更加普遍。报道了在脑和子宫中两者有相同的分布(Ardaillou,J.Am.Soc.Nephrol.,10,S30-39(1999))。在成人个体中的一些研究似乎证实了:在响应下列AngII刺激的调节中,AT2受体的活化作用与由AT1受体介导的那些活化作用具有相反的影响。
AT2受体还已经显示出参与细胞凋亡和细胞增殖的抑制(参见上述deGasparo等)。此外,AT2受体似乎在血压控制中起作用。Jones等(Pharmacology&Therapeutics120(2008)292-316)探讨了在心血管疾病中的AT2受体的功能相关性。在病理情况下,例如血管损伤、伤口愈合和心脏衰竭中,已经显示出AT2受体表达的增加(参见上述deGasparo等)。
上述deGasparo等大体描述了AT2受体的激动剂的预期药理作用。AT2受体激动剂已经显示出在治疗和/或预防消化道的疾病(例如消化不良和肠易激综合症)以及多器官功能衰歇中潜在的功效(参见WO99/43339)。
在其它欧洲专利申请EP409332、EP512675;国际专利申请WO94/27597、WO94/02142、WO95/23792和WO94/03435以及美国专利Nos5091390、5177074、5412097、5250521、5260285、5376666、5252574、5312820、5330987、5166206、5932575和5240928中已经公开了AngII拮抗剂(其结合到AT1和/或AT2受体)。US2009/326026公开含咪唑的三环化合物作为AT2激动剂的应用。WO2004046128涉及用作AT2受体的选择性激动剂的双环化合物。
例如,在国际专利申请WO00/38676、WO00/56345、WO00/09144、WO99/58140、WO99/52540、WO99/46285、WO99/45945、WO99/42122、WO99/40107、WO99/40106、WO99/39743、WO99/26644、WO98/33813、WO00/02905和WO99/46285;US5834432;以及日本专利申请JP143695中已经公开了肽和非肽AT2受体激动剂及其潜在应用,而这里描述的这些肽和非肽AT2受体激动剂未进行结构上评述。
由于AT2受体作为用于治疗的重要的新靶向(在高血压患者的整体护理中)的最新认识,本发明人着手于识别进一步有效的和/或选择性的AT2受体激动剂,期望该有效的和/或选择性的AT2受体激动剂在上述具体病症中具有功效。出乎意料地发现了以位于N-末端的额外的氨基酸延伸的Ang(1-7)的硫醚环化的肽类似物是AT2受体的潜在激动剂。
发明内容
因此,本发明提供一种环肽化合物或所述环肽化合物的药学可接受的盐,所述环肽化合物由氨基酸序列Xaa1-Asp-Arg-Ile/Val-Xaa5-Ile/Val-His-Xaa8组成,所述氨基酸序列Xaa1-Asp-Arg-Ile/Val-Xaa5-Ile/Val-His-Xaa8包括Xaa5和Xaa8的侧链之间的硫醚桥键,从而Xaa5和Xaa8一起形成根据通式中的任一种的结构:
其中,R、R1、R2、R3、R4和R5分别选自-H,低级(例如C1-C10)烷基或芳烷基,
以及其中,Xaa1选自由带电氨基酸、芳香族氨基酸和疏水性氨基酸以及它们的抗蛋白酶变体组成的组。
在下文中,肽化合物和盐一起被称为“本发明的化合物”。
药学可接受的盐包括酸式盐(acidadditionsalt)和碱式盐(baseadditionsalt)。这些盐的实例为:与例如盐酸、氢溴酸、硫酸、磷酸、硝酸等无机酸形成的酸式盐。盐还可由有机酸形成,有机酸例如乙酸、草酸、酒石酸、琥珀酸、马来酸、反丁烯二酸、葡萄糖酸、柠檬酸、苹果酸、抗坏血酸、安息香酸、鞣酸、帕莫酸、褐藻酸、多聚谷氨酸等。盐(例如鞣酸锌盐)可由多价金属阳离子或有机阳离子形成,多价金属阳离子例如锌、钙、铋、钡、镁、铝、铜、钴、镍等;有机阳离子由N,N'-二苄基乙二胺或乙二胺或它们的组合形成。无毒的生理学可接受的盐是优选的。这些盐可由常规方法形成,例如,可选地在该盐不溶的溶剂或培养基中通过本发明的化合物的游离酸或游离碱形式与同样当量或更多当量的合适的酸或碱的进行反应,然后利用标准技术(例如在真空中或通过冷冻干燥法)移除所述溶剂或所述培养基。也可以通过本发明的化合物的反离子的盐的形式与其他反离子的交换(例如利用合适的离子交换树脂)来制备上述盐。
优选地,R、R1、R2、R3、R4和R5分别选自H和CH3。
经发现,AT2受体相互作用需要在上述分子式的5位和8位处连接氨基酸的羊毛硫氨酸环(lanthioninering)。此外,由于发现第二额外的残基破坏AT2受体相互作用,所以N-末端延伸部应当限制为单个氨基酸残基。
在一个实施方式中,本发明提供一种肽,所述肽包括:根据分子式A的硫醚桥,也即,其中,在5位和8位的氨基酸之间的键具有-RCR1-S-R2CR3-的意义,其中,R、R1、R2和R3分别选自-H、低级(例如C1-C10)烷基或芳烷基。优选地,R、R1、R2和R3分别选自H和CH3。包括根据分子式A的硫醚桥的肽可例如由羊毛硫氨酸酶制得或由二硫化物的硫挤出(sulfurextrusion)来制得。通过在5位的D-半胱氨酸和在8位的L-半胱氨酸或通过5位的一个D-半胱氨酸和在8位的L-青霉胺可形成从其中挤出硫的二硫化物(Galande,Trent和Spatola2003Biopolymers71,534-551)。
或者,两个氨基酸的连接体可由RCR1-R2CR3-S-R4CR5(分子式B)或RCR1-S-R4CR5-R2CR3(分子式C)构成,其中,R、R1、R2、R3、R4和R5分别表示-H、低级(例如C1-C10)烷基或芳烷基。因此,包括根据分子式B的硫醚桥的肽例如可通过由在5位的D-高半胱氨酸和8位的L-半胱氨酸形成的二硫化物的硫挤出制得(Galande,Trent和Spatola2003Biopolymers71,534-551)。同样,因此,包括根据分子式C的硫醚桥的肽例如可通过由在5位的D-半胱氨酸和在8位的L-高半胱氨酸形成的二硫化物的硫挤出制得(Galande,Trent和Spatola2003Biopolymers71,534-551)。
方便的是,本发明的肽类似物能够在生物***中制得,尤其利用(细菌)宿主细胞的羊毛硫氨酸酶***。因此,包括根据分子式A的硫醚桥的肽是优选的。
在一个方面中,Xaa1为带正电的氨基酸,优选地为赖氨酸或精氨酸或抗肽酶变体或它们的衍生物。在另一方面中,Xaa1为带负电的氨基酸,优选地为天冬氨酸、谷氨酸或抗肽酶变体或它们的衍生物。或者,Xaa1为疏水性氨基酸,优选地为Ile、Leu或Val;或者Xaa1为芳香族氨基酸,优选地为Tyr或Phe或抗肽酶变体或它们的衍生物。抗肽酶变体或衍生物能保护类似物不被氨基酸肽酶降解。在一个实施方式中,Xaa1是抗肽酶氨基酸变体或衍生物,例如D-构型的上述氨基酸中的一种。其它合适的衍生物包括那些使游离氨基环化以形成环结构的衍生物,如焦谷氨酸(pGlu),其中终端是内酰胺环。
2、3、4、6和7位处的残基可为各种各样的,只要生物学活性得以保持即可。在优选的实施方式中,Xaa2是Asp,Xaa3是Arg,Xaa4是Val,Xaa6是Ile和/或Xaa7是His。硫醚桥中涉及的残基的立体化学可为L-形或D-形。其中,Xaa5为D-立体异构体和/或Xaa8为L-立体异构体的环肽是优选的。最优选的是其中Xaa5为D-立体异构体并且Xaa8为L-立体异构体的类似物。
血管紧张素-(1-7)的硫醚环化的类似物在本领域中是已知的。例如,参见Kluskens等(JPharmacolExpTher.2009Mar;328(3):849-54)和WO2008/130217。例如,在WO99/40106、WO99/52540和WO96/39164K中,Rodgers等已经描述了带有或不带有1至3个氨基酸的N-末端延伸部的线性血管紧张素类似物。然而,在本领域中未教导或提及具有选自带电氨基酸、芳香族氨基酸和疏水性氨基酸的单个残基的N-末端延伸部的cAng(1-7)类似物。
根据本发明的具体实施方式,在假定所述肽不含有两个Abu(2-氨基丁酸)残基时,环肽化合物选自由
Lys-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala(简称“K-cAng(1-7)”)
Asp-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala(简称“D-cAng(1-7)”)
Tyr-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala(简称“Y-cAng(1-7)”)
Ile-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala(简称“I-cAng(1-7)”)
Asn-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala(简称“N-cAng(1-7)”)
所组成的组。根据作为强有效的血管舒张肽的效力,尤其优选的是化合物K-cAng(1-7)和Y-cAng(1-7)。
由于本发明的化合物具有药理学活性,所以是有用的。因此,本发明的化合物可被表示为医药品。具体地,例如在下列测试中所证实的,本发明的化合物是AT2受体的激动剂,并且尤其是AT2子受体的选择性激动剂。本发明的化合物被预期在表达AT2受体且期望或需要AT2刺激的病症中是有用的。
本发明的化合物进一步被表明用于以血管收缩、增加的细胞生长和/或细胞分化、增加的心脏收缩力、增加的心血管肥厚,和/或增加的流体和电解质保留为特征的病症的治疗中。此外,本发明的化合物被表明用于涉及压力相关失调的治疗中,和/或在微循环和/或黏膜保护机制的改进中。因此,本发明的化合物被预期在在失调的治疗中是有用的,失调如上所述,并且例如胃肠道、心血管***、呼吸道、肾脏、眼、女性生殖(卵巢)***和中枢神经***(CNS)的失调。还提供了一种用于促进组织修复的方法,包括:将治疗有效剂量的根据本发明的肽化合物施用给需要它们的受试者。
可能提及的胃肠道的失调包括食管炎、巴雷特食管、胃溃疡、十二指肠溃疡、消化不良(包括非溃疡性消化不良)、胃食管反流、肠易激综合症(IBS)、炎性肠病(IBD)、胰腺炎、肝功能紊乱(例如肝炎)、胆囊疾病、多器官功能衰竭(MOF)和脓毒症。可能提及的其它胃肠道失调包括:口腔干燥、胃炎、胃轻瘫、胃酸过多、胆道的失调、腹痛(coelicia)、克罗恩病、溃疡性结肠炎、腹泻、便秘、疝气、吞咽障碍、呕吐、反胃、消化不良和综合症。可能提及的呼吸道疾病包括:炎性疾病,例如哮喘、阻塞性肺疾病(例如慢性阻塞性肺疾病)、肺病、肺动脉高血压和急性呼吸窘迫综合症。可能提及的肾脏疾病包括肾功能衰竭、肾炎和肾性高血压。可能提及的眼睛的疾病包括:糖尿病视网膜病变、早产儿视网膜病变和视网膜微动脉损伤(retinalmicrovascularisation)。可能提及的女性生殖***的疾病包括:***功能障碍。可能提及的心血管疾病包括:高血压、心脏肥大、心衰竭、动脉粥样硬化、动脉血栓、静脉血栓、血管内皮功能障碍、血管内皮病变、后球囊扩张狭窄、血管生成、糖尿病并发症、微血管功能障碍、心绞痛、心律不齐、间歇性跛行(claudicatiointermittens)、先兆子痫、心肌梗死、再梗死、缺血性病变、***功能障碍和新生内膜增生。可能提及的CNS的疾病包括:认知功能障碍、食物摄入量的功能障碍(饥饿/饱足感)以及口渴、中风、脑出血、脑栓塞和脑梗塞。本发明的肽化合物也用于使红血球增多,例如通过使有效量的至少一种肽化合物与红系祖细胞接触用来使红血球增多。
本发明的化合物在生长代谢和增殖的调节中也能是有用的,例如在增生性疾病、***增生症、自身免疫性疾病、牛皮癣、肥胖、神经细胞再生、溃疡的愈合、抑制脂肪组织增生、干细胞分化和增殖、癌症(例如,在胃肠道中,肺癌等)、细胞凋亡、肿瘤(广义)、肥大、糖尿病、神经病变、器官排斥的治疗中是有用的。
本发明的化合物被表明用于上述病症的治疗性和/或预防性治疗。
根据本发明的另一方面,因此提供本发明的化合物用作医药品。还提供一种药物组合物,包括:至少一种本发明的肽化合物以及药学可接受的载体和/或辅料。该药物组合物含有根据本发明的化合物与适用于肠内给药或肠胃外给药的有机或无机载体的混合物。因此,药物组合物可被配制成固体冻干,其中,不与肽发生反应的各种惰性化合物例如烃类可被用作载体。当药物组合物被配制成稀的或浓的悬浮液或乳液时,它们也含有各种防腐剂和稳定剂。可被引入片剂、胶囊等的辅料的实例如下:粘结剂,例如西黄蓍胶、***胶、玉米淀粉或明胶;赋形剂,例如微晶纤维素;崩解剂,例如玉米淀粉、预胶化淀粉、褐藻酸等;润滑剂,例如硬脂酸镁;甜味剂,例如蔗糖、乳糖或糖精;调味剂,例如薄荷、冬青油或樱桃。当制剂单元形式为胶囊时,除了上述类型的材料外,其可含有液体载体,例如脂肪油。各种其他材料也可作为涂层存在或用于修饰药剂单元的物理形式。例如,片剂可涂覆有虫漆、糖,或虫漆和糖。糖浆或酏剂可含有活性化合物、作为甜味剂的蔗糖、作为防腐剂的甲基和乙基帕拉胶、染料和调味剂(例如樱桃或桔子口味)。
根据本发明的另一方面,提供一种治疗如下病症的方法,该病症包括AT2受体激动剂的内源性生产不足的病症,和/或期望或需要增大AT2受体激动剂的影响的病症,和/或表达AT2受体且期望或需要AT2受体的刺激的病症,该方法包括:将治疗有效剂量的本发明的化合物给药至患有这种病症或易受这种病症感染的人。
本发明的化合物通常以药学可接受的药剂形式通过口服给药、静脉给药、皮下给药、口腔给药、直肠给药、真皮给药、鼻腔给药、气管给药、支气管给药,通过任何其他肠胃外途径或经由吸入给药。
当待治疗的病症是多器官功能衰竭时,优选的给药途径是肠胃外给药(例如通过注射)。否则,用于本发明的化合物的优选的给药途径是口服。本发明的化合物可单独给药,但是优选通过已知的药物制剂给药,该药物制剂包括用于口服给药的片剂、胶囊或酏剂;用于直肠给药的栓剂;用于肠胃外给药或肌肉给药的无菌溶液或悬浮液等。根据标准和/或可接受的药学实践可制备这些制剂。
因此,根据本发明的其他方面,提供一种药物制剂,所述药物制剂包括:本发明的化合物与药学可接受的辅料、稀释剂或载体的混合物。
本发明的化合物还可与本领域已知的其它AT2激动剂组合给药,以及与本领域已知的AT1受体拮抗剂(例如losartan)组合给药,或与血管紧张素转换酶(ACE)的抑制剂组合给药,或与Mas受体激动剂(例如4,7-环基血管紧张素-(1-7))组合给药或血管紧张素转换酶2(ACE2)组合给药。
在具体方面中,本发明涉及本发明的化合物在促进组织的生长或组织愈合中的应用。例如,提供一种根据本发明的肽化合物用于组织修复的应用。还提供一种用于促进伤口愈合的组合物,包括:合适的载体或稀释剂,以及对促进伤口愈合有效量的至少一种本发明的肽化合物。该化合物可以以基质溶液或胶束溶液(matricalormicellarsolution)给药。在一个实施方式中,该化合物在合适的载体或稀释剂中以至少0.1ng每kg体重的比率给药。载体或稀释剂可选自由羧甲基纤维素制剂、类晶体制剂、粘弹体、聚乙二醇和聚丙二醇所组成的组。有利地,上述化合物可与伤口绷带联合给药。
根据本发明的又一方面,提供一种复合产品,包括(A)本发明的肽化合物;以及(B)选自AT1受体拮抗剂或ACE抑制剂;和/或(C)Mas受体激动剂或ACE2,其中,每种成分(A)、(B)和/或(C)以与药学可接受的辅料、稀释剂或载体的混合物配制。这种复合产品提供用于本发明的化合物与AT1受体拮抗剂或ACE抑制剂,Mas受体激动剂或ACE2的联合给药,且因此可以以单独的制剂存在,其中,这些制剂中的至少一种包括本发明的化合物,且这些制剂中的至少一种包括AT1受体拮抗剂,或ACE抑制剂;或可作为联合制剂存在(配制)(即,以包括本发明的化合物和AT1受体拮抗剂或ACE抑制剂的单一制剂存在)。
因此,进一步提供:(1)药物制剂,包括:本发明的化合物和AT1受体拮抗剂或ACE抑制剂或Mas受体激动剂,或ACE2与药学可接受的辅料、稀释剂或载体的混合物,以及
(2)试剂盒部分,包括下列成分:
(a)药物制剂,包括:本发明的化合物与药学可接受的辅料、稀释剂或载体的混合物;以及
(b)药物制剂,包括:AT1受体拮抗剂或ACE抑制剂;
(c)Mas受体激动剂或ACE2与药学可接受的辅料、稀释剂或载体的混合物,其中,成分(A)、(B)和(C)各自以适用于联合其它成分给药的形式提供。
根据疾病和待治疗的病人以及给药的途径,本发明的化合物可以变化剂量给药。
尽管剂量从病人到病人而有所不同,在单一剂量给药时,例如用于皮下给药的合适的剂量在每个病人约1到1000微克/kg/天的范围内。更优选地,每日剂量在每个病人40至80微克/kg/天的范围内。进入静脉的剂量和皮下剂量是相同的。肺剂量(pulmonarydoses)为皮下剂量的约4倍。口服剂量为皮下剂量的至少5倍,并且强烈依赖于施用的制剂。本发明的化合物也可每周给药一次。周剂量为日剂量的约10至30倍。
在任何情况下,医生或技术人员将能够决定最适用于各个病人的实际剂量,这相应于将要治疗的病症以及将要治疗的具体病人的年龄、体重、性别和反应而变动。上述提到的剂量是平均情况下的实例,当然,个别的实例可高于或低于得到的剂量范围,并且这些是在本发明的范围内。本发明的化合物具有的优点是,它们选择性地结合至AT2受体并且在AT2上显示出激动剂活性。通过“选择性地结合”到AT2受体的化合物,我们总结了用于相关化合物的亲和性比例(AT2:AT1)为至少5∶1,优选至少10∶1,并且更优选地至少20∶1。本发明的化合物还可具有的优点是,它们与现有技术已知的化合物相比,可更有效,更低毒、更长的作用、更有效力、产生更少的副作用、更加易于吸收、和/或具有更好的药物代谢动力学模式(例如更高的口服生物利用度和/或更小的清除率),和/或具有其它有用的药学、物理或化学性质。
附图说明
图1.KcAng-(1-7)和YcAng-(1-7)是高度有效的血管舒张剂。
KcAng-(1-7)和YcAng-(1-7)诱导SpragueDawley大鼠的主动脉的苯肾上腺素预收缩(phenylephridine-precontracted)的环的血管舒张。×:对照;□:天然血管紧张素-(1-7);■:cAng-(1-7);○:KcAng-(1-7);●:YcAng-(1-7)。
图2.N-延伸的cAng-(1-7)类似物需要4,7-硫醚环以用于经由AT2受体的激动作用。
cAng-(1-7)是4,7-硫醚桥接的Ang-(1-7)。XcAng-(1-7)是在1位(即上文标记为Xaa1的残基)带有一个可变的额外的氨基酸的cAng-(1-7),其诱导Erk1(图2A)和Erk2(图2B)以及整个Erk磷酸化(图2C)。空白柱(openbar):对照;阴影柱:肽诱导的Erk磷酸化;黑色柱:在用AT2受体拮抗剂PD123319预处理后肽诱导的Erk磷酸化。在柱状图(图2A和图2B)中,表明在XcAng-(1-7)的1位的氨基酸“X”的识别。用PD123319预处理并不影响ScAng-(1-7)诱导的Erk2磷酸化(图2B),也不影响线状-DDRVAIHA诱导的整个Erk磷酸化(图2C)。dKcAng-(1-7)是带有赖氨酸的D-异构体的N-末端延伸部的cAng-(1-7)。
图3.通过带有两个氨基酸N-末端延伸的cAng-(1-7)类似物并不发挥AT2受体刺激。A组:在HBE细胞中的Erk1的DcAng-(1-7)和IcAng-(1-7)诱导的Erk1磷酸化。B组:在HBE细胞中,IDcAng-(1-7)和IDDRVAIHA-诱导的整个Erk磷酸化。空白柱:对照;阴影柱:肽诱导的Erk磷酸化而不进行HBE细胞的预处理;黑色柱:在用PD123319预处理后的肽诱导的ERK磷酸化。
图4.N-延伸的cAng-(1-7)类似物经由Mas受体并不产生作用。
Mas受体拮抗剂D-Pro7并不抑制SpragueDawley大鼠的主动脉的苯肾上腺素预收缩的环的KcAng-(1-7)-和YcAng-(1-7)-诱导的血管舒张。×:对照;○:KcAng-(1-7);:KcAng-(1-7)和Mas受体拮抗剂D-Pro7;●:YcAng-(1-7),▼:YcAng-(1-7)和Mas受体拮抗剂D-Pro7。
具体实施方式
实施例
实例1KcAng-(1-7)和YcAng-(1-7)是有效的血管舒张剂。
本实例证实了N-延伸的cAng-(1-7)类似物能够在来自SpragueDawley大鼠的预收缩的主动脉环中强烈地诱导血管舒张。
材料和方法
肽:KDRVdCIHC和YDRVdCIHC,购买自JPT,其中dC表示D-半胱氨酸。使用体重为350至450克的无特定病原体的雄性SpragueDawley(SD)大鼠(Harlan,zeist,荷兰)。在实验之前,动物被一起安置在温度和湿度可控制的房间中,自由接近自来水和固体饲料(Harlan,zeist,荷兰),并且给予12/12h明亮/黑暗周期。所有描述的协议通过格罗宁根大学委员会对动物实验的批准。
硫醚桥接的肽由如前述的二硫化物桥接的肽经由碱辅助的硫挤出来得到(GalandeAK等2003.Biopolymers71:534-551)。
在预收缩的主动脉环上的血管舒张。如前所述制备用于器官浴实验(organbathexperiment)的动脉环(KluskensLD,等.2009.JPharmacolExpTher328:849–54)。在测试肽的血管舒张效果之前,用30nM苯肾上腺素(PE)将环预收缩至它们最大收缩水平的50%。加入累积在0.1nM至1μM范围内的5,8-硫醚桥接的肽KDRV[AIHA]c或YDRV[AIHA]c。以30nMPE收缩的松弛的百分比来表示血管舒张数据。
结果图1证实了KcAng-(1-7)和YcAng-(1-7)对诱导来自SpragueDawly大鼠的预收缩的主动脉环的血管舒张的能力。这两种肽在子-nM浓度已经具有显著的血管舒张能力。
结论这些数据证实了KcAng-(1-7)和YcAng-(1-7)是高度有效的使血管舒张的肽。
实例2N-延伸的cAng-(1-7)类似物需要4,7硫醚环用于经由AT2受体的激动作用。
引言该实例显示出了如果以一个N-末端氨基酸延伸,硫醚桥接的cAng-(1-7)刺激人体支气管上皮(HBE)细胞中的细胞外信号调节激酶(ERK)磷酸化的能力。上述硫醚桥接的肽的AT2受体特异性是建立在测量肽诱导的ERK磷酸化是否能够通过PD123319(一种熟知的AT2受体的拮抗剂)来抑制。此外,该实例证实了对于经由AT2受体的激动作用需要N-末端延伸的类似物中的硫醚环。
材料和方法
肽购买自JPT:线性DDRVAIHA、dKDRVdCIHC、KDRVdCIHC、DDRVdCIHC、IDRVdCIHC、NDRVdCIHC、SDRVdCIHC,其中,dK表示D-赖氨酸,并且dC表示D-半胱氨酸。AT2受体拮抗剂PD123319来自AxonMedchem。利用生化人支气管上皮细胞系HBE进行研究(CozensAL等.1994CFTRexpressionandchloridesecretioninpolarizedimmortalhumanbronchialepithelialcells.AmJRespirCellMolBiol10:38-47)。所有的培养基和补充物、多孔板和烧瓶来自PAA。
细胞培养。多孔板容纳1ml来自涂布溶液(对于112ml:F12培养基100ml;牛血清白蛋白:10ml(1mg/ml);牛I型胶原蛋白:1ml(3mg/ml);人纤维蛋白:1ml(1mg/ml))并且在37°C和5%CO2下温育6小时。随后,去除涂布溶液,并且将板在层流柜中干燥2小时。在每个12孔板中,每孔接种8.104HBE细胞,随后在37°C和5%CO2下温育24小时。通过将432.2mlMEM199基础培养基加入到50ml(15%)FCS和5mlL-谷氨酸(200mM),10ml青霉素/链霉素(10.000单位/ml/10mg/ml)和2.8ml庆大霉素(10mg/ml)中来制备细胞培养基。用不含有FCS和生长因子的培养基代替85-90%融合培养基(confluencymedium),随后在37°C和5%CO2下再温育24小时。
Erk1和Erk2磷酸化。从每个孔中移除培养基,并用不含钙和镁的HBS缓冲液冲洗一次。在用10-6M的PD123319或伴随对照(concomitantcontrol)预孵化20分钟,然后洗涤后来测试在10-6M的肽的能力。在10分钟内在1ml/孔上进行激发(challenge)和伴随对照。所有的样品测试三次。在激发后,将150μlRIPA缓冲液(RIPA,TBS,1%诺尔洗涤液P-40,0.5%脱氧胆酸钠,0.1%SDS,0.004%叠氮化钠,1%PMSF(2mM最终浓度),1%矾酸钠(1mM最终浓度)和1%蛋白酶抑制剂混合物)加入到每个孔中。板在4°C下温育15分钟。从表面刮离裂解的细胞。将裂解液转移到1.5ml离心杯中并且在12.700xg下离心5分钟以收集细胞碎片。将上清液转移到新的杯子中,并且根据劳里法经由DC蛋白分析仪(Bio-Rad)以BSA作为校准蛋白测定5μl样品的总蛋白含量。在凝胶上分离蛋白并用p-ERK小鼠单克隆IgG2a和小鼠GAPDH抗大鼠IgG1抗体以及作为第二抗体的山羊抗小鼠IgG-AP进行印迹。用BCIP/NBT使磷酸化的Erk蛋白和GAPDH染色并且利用TotalLab软件确定相对于GAPDH和总Erk的量。或者,在使未分离的细胞透化后,测量总Erk磷酸化。
结果图2A显示出了:在N-末端具有一个氨基酸延伸的cAng-(1-7)类似物刺激ERK1和在较小程度上刺激ERK2的磷酸化。ERK1和ERK2磷酸化能够通过AT2拮抗剂PD123319抑制。AT2拮抗剂PD123319能够抑制肽诱导的ERK磷酸化的程度依赖于在N-末端延伸的“-1”位的氨基酸。在延伸的位置为Asp、Lys和Ile的情况下,ERK磷酸化完全被PD123319抑制。当在延伸的位置存在Asn或Ser时,ERK1磷酸化的抑制较小,并且ERK2磷酸化的抑制也较小或没有。图2C证实了:线性肽DDRVAIHA诱导的Erk磷酸化,但是对于该线性肽,诱导的Erk磷酸化将不能被PD123319抑制。另一方面,由硫醚桥接的dKcAng-(1-7)诱导的Erk磷酸化可以被PD123319抑制。
结论这些数据清楚地证明了:带有单个氨基酸N-末端延伸部的cAng-(1-7)经由AT2受体刺激ERK磷酸化。N-末端延伸的cAng-(1-7)的AT2受体的相互作用依赖于正好在N-末端“-1”位置的氨基酸。在该N-末端位置“-1”(在本文其它地方表示为Xaa1),带正电的氨基酸或带负电的氨基酸或疏水性氨基酸导致高AT2受体特异性;以无净电荷的疏水性氨基酸(例如Ser和Asn)延伸的肽不与AT2受体相互作用或难以与AT2受体相互作用。由于AT2拮抗剂PD123319不能抑制由线性N-延伸的Ang-(1-7)类似物诱导的ErK磷酸化,所以需要硫醚环用于N延伸的cAng-(1-7)肽经由AT2受体的作用。
实例3带有两个氨基酸N-末端延伸部的cAng-(1-7)类似物并不施加AT2受体刺激。
引言在该实例中,研究了带有两个氨基酸的N-末端延伸部的cAng-(1-7)类似物是否刺激AT2受体。在实例2中,测量在HBE细胞中肽诱导的ERK磷酸化,以及该磷酸化对AT2拮抗剂PD123319的依赖性。
材料和方法
硫醚桥接的肽的合成以及细胞培养和Erk1,以及总Erk磷酸化的测量与实例2中基本一致。
结果图3A显示出:硫醚桥接的类似物IcAng-(1-7)和DcAng-(1-7)两者诱导的Erk1磷酸化,该Erk1磷酸化能通过用PD123319预处理来抑制。然而,在两个氨基酸延伸部如在IDcAng-(1-7)中的情况下以及在线性IDDRVAIHA诱导的Erk磷酸化的情况下,用AT2拮抗剂PD123319的预处理根本未能得到抑制(图3B)。
总结实例2已经证实了对于N-延伸的Ang-(1-7)的AT2受体刺激需要环。一致地,具有线性变体的两个氨基酸的延伸部也不刺激AT2受体。由于以两个氨基酸N-末端延伸的非线性cAng-(1-7)也不刺激AT2受体,可以总结出cAng-(1-7)的一个氨基酸N-末端延伸部是AT2受体激动剂的N-末端延伸部限定。
实例4N-延伸的KcAng-(1-7)类似物并不经由Mas受体作用。
引言在该实例中证实了Mas受体拮抗剂DPro7-Ang-(1-7)不能抑制来自SpragueDawley大鼠的预收缩的主动脉环中的KcAng-(1-7)和YcAng-(1-7)诱导的血管舒张。
材料和方法
D-Pro7-ang-(1-7),在7位具有脯氨酸的D-异构体的ang-(1-7),是Mas受体拮抗剂,其购自JPT且在使用之前通过HPLC进行纯化。如Kluskens等,2009中以0.1μM的浓度在30nMPE的加入前10min使用该拮抗剂。其它材料和方法如实例1。
结果图4证实了Mas受体拮抗剂D-Pro7并不在SpragueDawley大鼠的预收缩的主动脉环中抑制KcAng-(1-7)和YcAng-(1-7)-诱导的血管舒张。
总结.KcAng-(1-7)和YcAng-(1-7)并未经由deMas受体作用。
Claims (24)
1.一种环肽化合物或所述环肽化合物的药学可接受的盐,所述环肽化合物由氨基酸序列Xaa1-Asp-Arg-Ile/Val-Xaa5-Ile/Val-His-Xaa8组成,所述氨基酸序列Xaa1-Asp-Arg-Ile/Val-Xaa5-Ile/Val-His-Xaa8包括Xaa5和Xaa8的侧链之间的硫醚桥键,从而Xaa5和Xaa8一起形成根据通式A的结构:
其中R、R1、R2和R3分别选自H和CH3,
以及其中,Xaa1选自由赖氨酸、酪氨酸、天冬氨酸和异亮氨酸组成的组。
2.根据权利要求1所述的肽化合物,其中,Xaa1为D-立体异构体。
3.根据权利要求1所述的肽化合物,其中,Xaa1为赖氨酸。
4.根据权利要求1所述的肽化合物,其中,Xaa1为天冬氨酸。
5.根据权利要求1所述的肽化合物,其中,Xaa1为异亮氨酸。
6.根据权利要求1所述的肽化合物,其中,Xaa1为酪氨酸。
7.根据权利要求1所述的肽化合物,其中,Xaa5为D-立体异构体。
8.根据权利要求1所述的肽化合物,其中,Xaa8为L-立体异构体。
9.根据权利要求1所述的肽化合物,其中,Xaa5为D-立体异构体并且Xaa8为L-立体异构体。
10.根据权利要求1所述的肽化合物,当该肽化合物不含有两个Abu残基时,所述肽化合物由氨基酸序列Lys-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala组成。
11.根据权利要求1所述的肽化合物,其中,所述肽化合物对AT2受体具有特异性。
12.根据权利要求11所述的肽化合物,其中,所述肽化合物是AT2受体的选择性激动剂。
13.根据权利要求10所述的肽化合物,其中,Lys是D-立体异构体。
14.根据权利要求1所述的肽化合物,其中,当该肽化合物不含有两个Abu残基时,所述肽化合物由氨基酸序列Tyr-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala组成。
15.根据权利要求1所述的肽化合物,其中,当该肽化合物不含有两个Abu残基时,所述肽化合物由氨基酸序列Asp-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala组成。
16.根据权利要求1所述的肽化合物,其中,当该肽化合物不含有两个Abu残基时,所述肽化合物由氨基酸序列Ile-Asp-Arg-Val-Abu/Ala-Ile-His-Abu/Ala组成。
17.一种药物组合物,所述药物组合物包括根据权利要求1至16中任一项所述的肽化合物和药学可接受的辅料、稀释剂或载体。
18.根据权利要求1至16中任一项所述的肽化合物在制备血管紧张素II-2型受体激动剂中的应用。
19.根据权利要求1至16中任一项所述的肽化合物在制备治疗和/或预防病症的药剂中的应用,在该病症的治疗和/或预防中期望和/或需要AT2受体的选择性激动。
20.根据权利要求19所述的应用,其中,所述病症为糖尿病、心血管疾病、高血压、心力衰竭、感染、脱发、贫血症、血细胞减少症、神经疾病、炎症、纤维化、癌症、急性呼吸窘迫综合症、伤口愈合、糖尿病并发症或肾脏疾病。
21.根据权利要求20所述的应用,其中,所述糖尿病为II型糖尿病。
22.根据权利要求20所述的应用,其中,所述肾脏疾病为肾炎、肾功能衰竭或肾性高血压。
23.根据权利要求19所述的应用,其中,所述病症为糖尿病视网膜病变。
24.一种复合产品,所述复合产品包括:(A)根据权利要求1至16中任一项所述的肽化合物;以及(B)选自AT1受体拮抗剂和ACE抑制剂的化合物;和/或(C)选自Mas受体激动剂和ACE2的化合物,其中,成分(A)、(B)和/或(C)中的每一种被配制在与药学可接受的辅料、稀释剂或载体的混合物中。
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PCT/NL2011/050793 WO2012070936A1 (en) | 2010-11-23 | 2011-11-22 | Novel angiotensin type 2 (at2) receptor agonists and uses thereof |
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CN110333302A (zh) * | 2019-06-25 | 2019-10-15 | 武汉兴华智慧医药科技有限公司 | 乙酰半胱氨酸溶液中n,n-二乙酰基羊毛硫氨酸的检测方法 |
EP4007592A1 (en) * | 2019-08-02 | 2022-06-08 | LanthioPep B.V. | Angiotensin type 2 (at2) receptor agonists for use in the treatment of cancer |
KR102488519B1 (ko) * | 2020-07-22 | 2023-01-13 | 순천대학교 산학협력단 | 신규 고리형 펜타뎁시펩타이드 화합물 및 이를 유효성분으로 함유하는 상처 치유 또는 재생용 조성물 |
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