CN102574894A - 稳定化的黑皮质素配体 - Google Patents
稳定化的黑皮质素配体 Download PDFInfo
- Publication number
- CN102574894A CN102574894A CN2010800384694A CN201080038469A CN102574894A CN 102574894 A CN102574894 A CN 102574894A CN 2010800384694 A CN2010800384694 A CN 2010800384694A CN 201080038469 A CN201080038469 A CN 201080038469A CN 102574894 A CN102574894 A CN 102574894A
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- CN
- China
- Prior art keywords
- melanocortin
- pro
- proline
- threonine
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明公开了用于非-天然存在的黑皮质素配体的组合物和方法,包括偶联于耐降解的C-端延伸(及任选地,N-端延伸)的黑皮质素类似物,以产生具有减小的或消除的心血管活性而保留期望的黑皮质素调控活性的稳定的黑皮质素配体。
Description
【技术领域】
本发明提供具有耐降解的C-端延伸以最小化或消除心血管效应的黑皮质素配体,其用于治疗各种病理学情况。
【背景技术】
以下讨论引用作者的许多出版物和出版物年。本文中提供该出版物的讨论来展现更完整背景,且不解释为承认该出版物是″现有技术″。
黑皮质素是结合于5种知道的黑皮质素受体(MC1R~MC5R)家族的一组小肽(Cone,R.D.,2006,Endocr.Rev.,27(7):736-749)。它们源于常见的前体蛋白,促-阿片黑皮质素(POMC),其在中枢和外周神经系统的神经元中,及垂体腺中表达(Voisey,J et al.,2003,Curr.Drug Targets,4(7):586-597)。POMC的蛋白水解切割除了几种其他生物学重要的肽之外,产生α-黑皮质素、β-黑皮质素及γ-黑皮质素和肾上腺皮质激素(ACTH)。
在5种知道的黑皮质素受体中,MC3R和MC4R被认为主要在哺乳动物脑中表达,MC3R在下丘脑的弓状核中最高度表达,及MC4R在丘脑,下丘脑和海马中表达。MC1R是主要在其被发现的周边表达,例如,在黑色素瘤细胞和黑色素细胞和免疫细胞中。在神经元系统中,MC1R仅存在于中脑的导水管周围灰质的神经元中,其中其被认为在控制疼痛中具有作用。MC2R是主要在肾上腺皮质中表达,其中其控制类固醇生成。MC5R主要见于外周组织诸如许多外分泌腺的分泌上皮,其中其影响分泌和营养控制。
起初认为黑皮质素肽具有主要针对皮肤色素沉着控制的生理学功能。但是,在最近25年,许多额外的生物学活性归因于黑皮质素。是激动剂(活化物)或拮抗剂(抑制剂)的黑皮质素肽已显示控制许多生理学过程,包括色素沉着,饲喂,总体代谢速度/能量稳态,内分泌和外分泌腺分泌,发炎,通过肾的钠排泄,疼痛感觉,成瘾行为和性冲动。
因此,已合成黑皮质素类似物用于潜在调节和治疗许多条件,包括重量调节(例如,肥胖症,厌食症和恶病质),激素分泌,及许多外分泌腺的分泌过少(例如,Sjogren氏综合征),免疫-关联病情和性功能障碍(Cone,R.D.,2006,Endocr.Rev.,27(7):736-749;Cone,R.D.,2005,Nat.Neurosci,8(5):571-578;Bazzani,C.,et al.,2002,Resuscitation,52(1):109-115;and Bertonlini,A.,et al.,2009,Pharmacol.Res,59(1):13-47)。但是,在调控这些生理学效应中,黑皮质素类似物也显示导致高血压(Gruber,et al.,1984,Hypertension,6:468-474and Klein,et al.,1985,Life Sci.36:769-775)。实验研究显示,黑皮质素类似物(配体)的施用增加动脉压力和心律,且可产生心律失常(Gruber and Callahan,1989,Am.J.Physiol.257:R681-R694;及未公开的数据)。
通过黑皮质素药效团:(His-Phe-Arg-Trp)(SEQ ID NO:1)达到黑皮质素肽的生理学调控效应;此药效团是黑皮质素-调控的活性必需的最小集合的氨基酸(Holder,J.R.and C.Haskel-Luevano,2004,Med.Res.Rev.,24(3):325-356)。一般而言,全部黑皮质素肽共享相同的活性核心序列:His-Phe-Arg-Trp(SEQ ID NO:1),包括促黑素神经肽和促肾上腺皮质素。在天然存在的黑皮质素肽中此核心序列周围的氨基酸被认为影响特定黑皮质素受体的相对亲和性。
已合成增强了黑皮质素受体的亲和性的各种非-天然存在的黑皮质素类似物。例如,Klemes et al.1986,Biochem.Biophys.Res.Commun.,137(2):722-728合成了黑皮质素类似物(Ac-Nle-Asp-His-D-Phe-Arg-Trp)和(Ac-Nle-Asp-His-Phe-Arg Trp)(SEQ ID NO:2)。这些修饰的类似物显示增加的促黑素活性潜力。已鉴定几种其他黑皮质素类似物。已合成的,具有增加的潜力的黑皮质素类似物的进一步例包括(Ac-Nle-环-Asp-His-Phe-Arg-Trp-Lys)和(Ac-Nle-环-Asp-His-D-Phe-Arg-Trp-Lys)(al-Obeidi et al.,1989,J.Med.Chem,32(12):2555-2561);(Ac-Nle-环-Asp-His-D-Nal2′-Arg-Trp-Lys)和(Ac-环-Cys-Glu-His-D-Nal2′-Arg-Trp-Gly-Cys-Pro-Pro-Lys-Asp)(Balse-Srinivasan et al.,2003,J.Med.Chem.,46(17):3728-3733);(Ac-Nle-Glu-His-D-Phe-Arg-D-Trp-Gly)(al-Obeidi et al.,1989,Pept.Res.,2(1):140-146);及(His-Phe-Arg-Trp-Gly-Lys-Pro-Val)(SEQID NO:3),(Masman et al.,2008,Bioorg.Med.Chem.,16(8):4347-58)。
但是,由于它们的强心血管副作用(Greenfield et al.,2009,N.Eng.J.Med.360:44-52;Gupta,2007,Reuters Aug.30,2007;Mishra,2007,Reuters Sept.10,2007;Nordheim et al.,2006,Peptides 27:438-443),至今合成的黑皮质素类似物尚未导致用于治疗许多黑皮质素-相关的病情之任何的政府调控机构批准的治疗性药物。黑皮质素类似物的临床无法接受的心血管效应由位于第1药效团之内的第2药效团(Arg-Trp)介导。(Klein et al.,1985,Life Sci.,36:769-775;Gruberand Callahan,1989,Am.J.Physiol.,257:R681-694)。此第2药效团被认为与RFamide受体家族的亚组相互作用,导致中枢交感神经激动的升高及心血管效应的起始。在或接近许多合成黑皮质素配体的C-端的Arg-芳族二-肽序列的一般化的基序是RFamide类的药效团的更包括性的描述(Gruber and Callahan,Am.J.Physiol.,1989,257:R681-694;Klein et al.,1985,Life Sci.36:769-775;Clements et al.,2001,Biochem.Biophys.Res.Commun.,284:1189-1193)。
尽管长期相信黑皮质素心血管效应不可从非-高血压,及潜在地治疗性,生理学效应分离,Gruber和Callahan显示这不正确(Gruber和Callahan 1989,Am.J.Physiol.,257:R681-694)。黑皮质素类似物的肽C-端延伸可最小化急性心血管活性,而保存黑皮质素效应。有效地,额外的C-端氨基酸通过在肽的分子结构之内更深运动暂时“隐藏”心血管/RFamide-样药效团(Arg-Trp)。此不影响黑皮质素活性地急性地抑制心血管效应。
虽然如此,在体外测定中已显示了最小化的心血管活性的黑皮质素类似物上的许多C-端延伸已显示体内降解。具有C-端延伸的黑皮质素类似物可起初仅赋予期望效果,但一旦降解发生,(Arg-Trp)RFamide药效团暴露,赋予关联的心血管效应。
【发明概述】
由于黑皮质素药物会潜在地用于处理慢性病情,它们不必需在延长的施用期间产生潜在地危险的副作用。由此,慢性施用期间的黑皮质素配体心血管效应的阻遏对于临床安全的黑皮质素药物重要。此需要自其治疗性黑皮质素效应的黑皮质素药效团的RFamide心血管作用的延长的体内分离。此会允许黑皮质素类似物用作用于各种病理学情况的治疗,伴随心血管病理学的最小风险。在本发明的第1方面,提供非-天然存在的黑皮质素配体及包含偶联于耐降解的C-端延伸的黑皮质素类似物,有效产生自RFamide心血管活性的黑皮质素的慢性分离。
在本发明的第2方面,提供非-天然存在的黑皮质素配体及包含偶联于耐降解的C-端延伸的黑皮质素类似物,其选自至少1种氨基酸,至少1种修饰的氨基酸,肽模拟物,及其组合。
在本发明的第3方面,提供非-天然存在的黑皮质素配体及包含偶联于耐降解的C-端延伸和耐降解的N-端延伸的黑皮质素类似物。
【发明详述】
提供组合物,其包含非-天然存在的黑皮质素配体,其偶联于耐降解的C-端延伸,以抑制RFamide/心血管药效团的暴露和效应,及任选地偶联于N-端延伸,以防止黑皮质素药效团的N~C-端(即,从左至右)酶促降解。耐降解的C-端延伸是至少1种氨基酸,至少1种修饰的氨基酸,肽模拟物(非-氨基酸小分子),或其组合。耐降解的C-端延伸选择为当急性地或慢性地施用于人或哺乳动物时抵抗在生理条件下降解,由此允许黑皮质素类似物维持至少一种黑皮质素生理学调控效应而呈现最小化的或消除的心血管效应的C-端延伸。
【术语】
黑皮质素类似物至少指黑皮质素药效团。黑皮质素类似物是在生理条件下结合黑皮质素受体的分子。黑皮质素类似物包括非-天然存在的黑皮质素多肽及黑皮质素全长蛋白或多肽的截短的和/或修饰的形式。例如,在由241个氨基酸组成的″亚-肽″的蛋白水解切割之前的全长POMC蛋白。POMC的组织-特异性蛋白水解切割产生跨13个氨基酸~76个氨基酸的尺寸的肽(Bicknell和Lawry,2000,Encyclopediaof Stress,vol.3,257-265,Academic Press)。本文讨论的增加了黑皮质素受体活性的合成的,非-天然存在的黑皮质素类似物是约7~12个氨基酸的尺寸。黑皮质素类似物呈现与黑皮质素受体的结合官能性。结合是活化(激动剂)或抑制性(拮抗剂)的。除了肽之外,黑皮质素类似物包括黑皮质素的小分子类似物或其部分,其包括有机或无机化合物,或肽和小分子-即,肽模拟物的组合。
黑皮质素类似物可与黑皮质素蛋白结构上类似和/或在它们结合黑皮质素受体的能力上功能性地类似。而且,黑皮质素类似物通常含有药效团:His-Phe-Arg-Trp(SEQ ID NO:1)或其修饰的形式,或其结构或功能肽模拟物。
肽模拟物是模拟肽(氨基酸链)或1个氨基酸残基的非-氨基酸分子。
药效团是达到生理学效应必需的氨基酸残基的最小集合;或是结合和活化受体需要的氨基酸残基的(对于受体)结构模拟物的小分子。His-Phe-Arg-Trp(SEQ ID NO:1)和它们的类似物是用于调控的生理学效应的黑皮质素的药效团。因此,非-天然存在的黑皮质素药效团类似物可为设计为模拟黑皮质素药效团核心序列肽的外观或功能(包括受体活性的活化或灭活)的小肽或有机分子。
心血管效应包括高血压的医学定义,即高血压的医学定义(至少120/80mm Hg以上,及尤其如果140/90mm Hg(心脏收缩/心脏舒张)以上),对血管系统,肾和心脏,及其他关联的效应的病理学效应。相反,低血压是当血压下落到医学上接受的标准以下时。心律失常暗示在动脉压力的脉动压力波的正常对称呈现中的改变。此可为增加的每分钟心跳(心动过速)或降低的每分钟心跳(心动过缓)。其也可暗示在心电图的正常波图案中的改变。
实质性降解指称可相比无C-端延伸的黑皮质素配体或黑皮质素类似物,本发明的黑皮质素配体的黑皮质素类似物的C-端延伸,N-端延伸,或其他区通过生理学酶和其他因素,以该方式或RFamide药效团通过RFamide受体或其他生理学系统再次能起始心血管效应的程度的降解。根据本发明的优选的方面,具有抵抗实质性降解的C-端延伸的黑皮质素类似物是相比缺乏C-端延伸的黑皮质素类似物,无大于50%,优选无大于25%,及更优选小于10%的施用的配体可重建心血管效应的黑皮质素类似物。
药物组合物包括本发明的配体,或其药学可接受的盐,及药学可接受的载体。载体可为液体制剂,例如,缓冲的,等渗性水溶液。药学可接受的载体也可包括赋形剂,诸如稀释剂,载体等,及添加剂,诸如稳定化剂,防腐剂,溶解剂,缓冲剂等。
药学可接受的盐指称自药学可接受的非-毒性碱或酸,包括无机和有机酸和碱制备的盐。源于无机碱的盐包括铝,铵,钙,铜,铁,亚铁,锂,镁,锰,二价锰,钾,钠,锌盐和类似盐。特别优选的是铵,钙,锂,镁,钾和钠盐。源于药学可接受的有机,非-毒性碱的盐包括伯,仲和叔胺,取代的胺,包括天然存在的取代的胺,环状胺和碱性离子交换树脂,诸如精氨酸,甜菜碱,咖啡因,胆碱,N,N′-二苄乙烯二胺,二乙基胺,2-二乙基氨基乙醇,2-二甲基氨基乙醇,乙醇胺,乙二胺,N-乙基-吗啉,N-乙基哌啶,葡萄糖胺,葡萄糖胺,组氨酸,海巴明,异丙基胺,赖氨酸,甲基葡萄糖胺,吗啉,哌嗪,哌啶,聚胺树脂,普鲁卡因,嘌呤,可可碱,三乙基胺,三甲胺,三丙基胺,缓血酸胺和类似碱性离子交换树脂的盐。
当本发明的化合物是碱性时,盐可从药学可接受的非-毒性酸,包括无机和有机酸制备。该酸包括乙酸,苯磺酸,苯甲酸,樟脑磺酸,柠檬酸,乙磺酸,甲酸,富马酸,葡萄糖酸,谷氨酸,氢溴酸,盐酸,羟乙磺酸,乳酸,马来酸,苹果酸,扁桃酸,甲基磺酸,丙二酸,粘酸,硝酸,双羟萘酸,泛酸,磷酸,丙酸,琥珀酸,硫酸,酒石酸,p-甲苯磺酸,三氟乙酸和类似酸。特别优选的是柠檬酸,富马酸,氢溴酸,盐酸,马来酸,磷酸,硫酸和酒石酸。
需知,如本文所用,式I和式II的化合物意指也包括这些化合物的药学可接受的盐,诸如盐酸盐,等。
化合物列中的缩写具有它们的常规含义。由此,″Nle″是正亮氨酸;″Nal″是正丙氨酸;″D-Nal″是D-正丙氨酸;″Asp″是天冬氨酸;″His″是组氨酸;″D-Phe″是D-苯丙氨酸;″Arg″是精氨酸;″Trp″是色氨酸;″Lys″是赖氨酸;″Gly″是甘氨酸;″Pro″是脯氨酸;″Tyr″是酪氨酸;″Ser″是丝氨酸;“Cys”是半胱氨酸;″Val″是缬氨酸;″D/L-Thr″是D-苏氨酸或L-苏氨酸;″D/L-Pro″是D-脯氨酸或L-脯氨酸。此外,″Ac″是N-乙酰和″环″指称环状结构,其在文献中也显示为″c″或指称为″内酰胺″。
额外的缩写定义如下:Nal(2′)=D-2′-奈基丙氨酸;tBu=叔-丁基;Hyp(Bzl)=苄基-L-羟基-脯氨酸;Mamb=3-氨基甲基-苯甲酸;戊二酸接头=CO-(CH2)3-CO;Pen=L-青霉胺;Aib=2-氨基异丁酸;Tic=1,2,3,4-四氢异喹啉-3-羧酸;Aba=4-氨基-1,2.4,5-四-氢-2-苯并氮-3-酮;Pip=哌啶-2-羧酸;Nip=哌啶-3-羧酸;Tic=四氢喹啉-3-羧酸;Bip=联苯胺;Phg=α-苯基-甘氨酸;Sar=肌氨酸;Azt=3′-叠氮基-3′-脱氧胸苷;Oic=八氢吲哚-2-羧酸。
【黑皮质素类似物】
在一实施方式中,非-天然存在的黑皮质素配体如式I所示,及包含偶联于耐降解的C-端延伸和任选的N-端延伸的黑皮质素类似物:
Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-X1-X2-X3(式I)
其中Y1-Y2-Y3代表任选的稳定化N-端残基或氨基酸残基模拟物;R1~R7代表黑皮质素类似物的残基;及X1-X2-X3代表耐降解的C-端残基或氨基酸残基模拟物。
总之,R1~R7(R1-R2-R3-R4-R5-R6-R7)可为许多知道的黑皮质素类似物之一,其中各7个残基是独立地氨基酸或肽模拟物。一些黑皮质素类似物具有小于7个残基。在另一实施方式中,R1~R7,共同,代表α黑皮质素类似物。在另一实施方式中,R1~R7,共同,代表结合作为激动剂或拮抗剂的MC3-MC5受体的黑皮质素类似物。
在一实施方式中,黑皮质素配体由以上式I所示,且残基R1~R7,共同,代表黑皮质素类似物,其中
R1缺失或选自:半胱氨酸,正亮氨酸,乙酰化的正亮氨酸,乙酰化的半胱氨酸,D-苯丙氨酸,甲基化的D-苯丙氨酸,琥珀酸,o-酞酸,酪氨酸,天冬氨酸,戊二酸,CO-顺式-CH=CH-CO,n-戊酰基,及n-己酰基;
R2缺失或选自:脯氨酸,天冬氨酸,谷氨酸,甘氨酸,半胱氨酸,正亮氨酸,精氨酸,琥珀酸,戊二酸,CO-顺式-CH=CH-CO,n-戊酰基,及n-己酰基;
R3选自:组氨酸,在第1或3位甲基化的组氨酸,D-脯氨酸,L-脯氨酸,D-Nal(2′),L-Nal(2′),琥珀酸,tButGly,Hyp(Bzl),Mamb,Oic,正亮氨酸,Aba,β-丙氨酸和Tic;
R4选自:组氨酸,D-苯丙氨酸,L-苯丙氨酸,D-Nal(2′),pCl-D-Phe和(o-Phe)Phe;
R5选自:精氨酸,高精氨酸,鸟氨酸,丙氨酸,脯氨酸,Pip,Nip,Tic,Phg,Sar和Azt;
R6选自:D-色氨酸,L-色氨酸,D-Nal(2′),L-Nal(2′),Tic和Bip;
R7缺失或选自:甘氨酸,谷氨酸,半胱氨酸,赖氨酸和2,3-二氨基-丙酸;
其中如果R3是Aba,则R4选自:D-Phe,D-Nal(2′)和pCl-D-Phe;以及
其中如果R2是n-戊酰基或n-己酰基,则R1,Y1,Y2和Y3缺失。
在另一实施方式中,本发明的黑皮质素配体如式II所示:
Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-R8-R9-X1-X2-X3(式II)。
总之,R1~R9(R1-R2-R3-R4-R5-R6-R7-R8-R9)可为许多知道的黑皮质素类似物之一,其中各9个残基是氨基酸或肽模拟物。一些黑皮质素类似物具有小于9个残基。在另一实施方式中,R1~R9,共同,代表γ黑皮质素类似物。在另一实施方式中,R1~R9,共同,代表结合作为拮抗剂的MC3受体的黑皮质素类似物。
在一实施方式中,黑皮质素配体如以上式II所示,及残基R1~R9,共同,代表黑皮质素类似物,其中:
R1是酪氨酸;
R2是缬氨酸;
R3选自:甲硫氨酸,正亮氨酸,半胱氨酸和L-青霉胺;
R4选自:甘氨酸,D-半胱氨酸,L-半胱氨酸,天冬氨酸,及正亮氨酸;
R5选自:组氨酸,正亮氨酸,脯氨酸和Aib;
R6选自:苯丙氨酸,D-Nal(2′)和L-Nal(2′);
R7是精氨酸;
R8选自:色氨酸和D-Nal(2′);以及
R9缺失或选自:天冬氨酸,半胱氨酸,青霉胺和赖氨酸。
在另一实施方式中,提供如式I或式II所示的黑皮质素配体,其中至少1个D-苯丙氨酸残基,或全部D-苯丙氨酸残基被卤化(例如,氟或氯),以赋予与其对应MC受体的改善的黑皮质素蛋白-配体相互作用(Ippolito,J.A and D.W.Christianson,1992,Int.J.Biol.Macromol,14(4):193-197)
【C-端延伸】
向式I的R1~R7黑皮质素类似物,或向式II的R1~R9(R1-R2-R3-R4-R5-R6-R7-R8-R9)黑皮质素类似物,提供C-端延伸,以便赋予C-端延伸的降解-抗性,以防止RFamide序列的暴露。
在一实施方式中,C-端延伸由式I的X1-X2-X3表示,其中
X1选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;
X2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;以及
X3缺失或选自:D-苏氨酸,L-苏氨酸,及哌嗪-2-酮环。
在另一实施方式中,C-端延伸由式II的X1-X2-X3表示,其中
X1选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;
X2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;以及
X3缺失或选自:D-苏氨酸,L-苏氨酸,及哌嗪-2-酮环。
在一实施方式中,C-端延伸具有慢性地抑制由羧基肽酶的降解的构象。慢性地抑制降解的C-端延伸的例包括D-Pro-D-Pro,D-Thr-D-Pro,D-Thr-D-Pro-D-Thr的二-及三肽,如描述于Tugyi et al.,2005,Proc.Nat.Acad.Sci.(USA),102(2):413-418。
在另一实施方式中,脯氨酸模拟物(哌嗪-2-酮环)取代D-Pro。在一种方法中,脯氨酸模拟物如Teixido,M.,et al.,2007,Brain Res.Bull.,73(1-3):103-107所述合成。哌嗪-2-酮环也讨论于Bhatt,U.andJust,G.,2000,Helvetica Chimica Acta,83:722-727。对于脯氨酸用哌嗪-2-酮环的取代而言,在2个相邻α-氨基的氮分子之间的乙烯桥合并。此产生含有2个氮和4个碳原子的6-元环,是类似于2个相邻氨基酸残基官能团之间的脯氨酸环(尽管6-元)的结构。
根据本发明的教导,黑皮质素类似物的C-端延伸在配体自人或动物身体内的血流清除之前耐受实质性降解。在一实施方式中,C-端延伸足够稳定,使得当施用于人或动物时,黑皮质素配体不导致心血管效应,或最小化了心血管效应。由于肽,氨基酸和小分子的稳定性广泛改变,本发明的黑皮质素配体在细胞外生理学环境中具有可变的长度C-端延伸。C-端延伸足够稳定(例如,长度,立体结构)使得在其自血流清除之前身体内的任何降解不会再暴露心血管药效团,以达到其效应。
【N-端延伸】
在本发明的一实施方式中,N-端延伸偶联于黑皮质素类似物。N-端延伸如式I中的Y1-Y2-Y3表示,其中
Y1缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸和L-脯氨酸;
Y2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;以及
Y3缺失或选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环。
在另一实施方式中,N-端延伸如式II中的Y1-Y2-Y3表示,其中
Y1缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸和L-脯氨酸;
Y2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;以及
Y3缺失或选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环。
【式I的黑皮质素配体的环化】
环化的黑皮质素类似物显示了改善的功效和稳定性(Balse-Srinivasan et al.,2003,J.Med.Chem.,46(17):3728-3733 andBednarek et al.,2001,Biochem.Biophys.Res.Commun.,286(3):641-645;Kavarana,et al.,2002,J.Med.Chem.,45(12):2644-2650)。在一实施方式中,将如式I所示的非-天然存在的黑皮质素配体环化。以下显示如何可将如式I所示的黑皮质素配体环化的例的非限制性列表:
当R1或R2是半胱氨酸和R7或X1是半胱氨酸时,R1或R2和R7或X1之间的二硫键如描述于Balse-Srinivasan et al.,2003,J.Med.Chem.,46(23):4965-4973。当X1是半胱氨酸时,X2不缺失,但选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸和哌嗪-2-酮环。
当R1是正亮氨酸和R7是谷氨酸时,R1和R7之间的内酰胺桥如描述于Mayorov et al.,2006,J.Med.Chem.,49:1946-1952,andBednarek et al.,2001,Biochem Biophys.Res.Commun.,286(3):641-645。
当R2是谷氨酸或天冬氨酸和R7是赖氨酸时,R2和R7之间的侧链内酰胺桥如描述于Bednarek et al.,2001Biochem Biophys.Res.Commun.,286(3):641-645。
当R1是琥珀酸或o-酞酸和R7是赖氨酸时,R1和R7之间的内酰胺闭合如描述于Bednarek et al.,2001,Biochem Biophys.Res.Commun.,286(3):641-645和Kavarana,et al.,2002,J.Med.Chem.,45(12):2644-2650。
当R2或R3是琥珀酸和R7是2,3-二氨基-丙酸时,R2或R3和R7之间的内酰胺闭合如描述于Bednarek et al.,2001,Biochem Biophys.Res.Commun.,286(3):641-645。
通过目的线性肽的N和/或C末端之间的共价键形成来形成“主链”环化的肽。此一例描述于经由烷基和酰胺组成的桥的2个酰胺氮的键合,如描述于Hess et al.,2007,J.Med.Chem.,50:6201-6211。
【氨基酸-异构体和非-标准氨基酸】
在一实施方式中,用于本发明的非-天然存在的黑皮质素配体的本文提供的氨基酸残基,可为D-或L-氨基酸或可用它们的非-标准物,异构对应物取代。例如,α氨基酸可用β氨基酸取代,及L氨基酸可用D氨基酸取代。本文公开的氨基酸不指定为D-或L-异构体,可为任何异构体。
【式II的黑皮质素配体的环化】
在另一实施方式中,将如式II所示的非-天然存在的黑皮质素配体环化。当R4是天冬氨酸和R9是赖氨酸时,可将如式II所示黑皮质素类似物通过R4和R9之间的内酰胺侧链环化,如描述于(Bednarek etal.,2001,Biochem Biophys.Res.Commun.,286(3):641-645和Mayorov et al.,2006,J.Med.Chem.,49:1946-1952)。
【用于MC受体结合的黑皮质素配体】
在一实施方式中,本发明的非-天然存在的黑皮质素配体是α黑色素细胞-刺激激素(MSH)基团的MC4受体激动剂,MC4受体拮抗剂,MC3受体激动剂,MC3受体拮抗剂,和/或MC5激动剂。
在另一实施方式中,本发明的非-天然存在的黑皮质素配体是γ黑色素细胞-刺激激素基团的MC3拮抗剂。
在另一实施方式中,本发明的非-天然存在的黑皮质素配体是γ黑色素细胞-刺激激素基团的MC3激动剂。
【肽的合成和延伸】
一般而言,公开的黑皮质素配体通过例如固相合成来合成,及根据本领域知道的方法纯化。将利用各种树脂和试剂的许多熟知的方法用于制备本发明的化合物。有机分子根据本领域知道的方法类似地合成。
本发明的配体可为任何药学可接受的盐形式。本发明的配体的酸加成盐在适合的溶剂中自分子和过量的酸,诸如盐酸,氢溴酸,硫酸,磷酸,乙酸,三氟乙酸,马来酸,琥珀酸或甲基磺制备。其中配体包括酸性部分,适合的药学可接受的盐可包括碱金属盐,诸如钠或钾盐,或碱土金属盐,诸如钙或镁盐。
在一实施方式中,肽通过固相方法通过使用游离C-端肽的p-苄氧基-苯甲醇树脂用手动合成制备。全部氨基酸作为9-芴基甲氧基羰基(Fmoc)-衍生物偶联,如描述于Fields et al.,1992,Synthetic Peptides:A User′s Guide,W.H.Freeman and Company,New York,77-183;及Fields and Noble,1990,Int.J.Peptide Protein Res.,35:161-214;Fieldset al.,1991,Peptide Res.4:95-101。简言之,叔-丁基在N,N-二甲基甲酰胺(DMF)中应用为用于1-羟基苯并三唑/N,N′二异丙基碳二亚胺原位活性酯方法的保护基。分别通过DMF中的20%哌啶,或DMF中的2%哌啶和2%二氮杂二环[5.4.0]十一碳-7-烯除去Fmoc基。通过茚三酮测试和/或靛红测定监控偶联及脱保护的成功。合成完成之后,将肽用含有5%水的三氟乙酸自树脂切割。通过RP-HPLC在Supelcosil C18柱上通过使用梯度洗脱用下列洗脱液进行粗产物纯化:A,水中的0.1%三氟乙酸;及B,乙腈/水(80∶20,vol/vol)中的0.1%三氟乙酸。用5%洗脱液B等度洗脱5min之后,经25分钟于室温及用4mL/min的流速产生0~25%B或5~30%B的线性梯度。以λ=214nm进行UV检测。通过分析RP-HPLC在Synergi(4.6mm×25cm,MAX-RP
4μm)柱上进行肽纯度研究。
以下参考文献公开合成本发明中具体化的残基和连接的方法。对于哌嗪-2-酮环-见Bhatt,U and Just,G,2000,Helvetica ChimicaActa,83:722-727;Mohamed,N.,et al.,1998,Tetrahedron Lett.,39:8213-8216;Teixido,M.,et al.,2007,Brain Res.Bull.,73(1-3):103-107。对于Nal(2′)-见Kavarana,MJ et al.,2000,J.Med.Chem.,45:2644-22650;and Holder,J.R.,et al.,2002,J.Med.Chem.,45:5736-5744。对于Aba-D-Phe,Aba-pCL-D-Phe和Aba-D-Nal(2′)的二肽模拟物-见Ballet,S.,et al.,Bioorganic&Med.Chem.Lett.,2007,17:2492-2498。对于OIC,BIP和PIP-见Bednarek,M.A.,et al.,2007,J.Med Chem,50:2520-2526。对于戊二酸接头-见Mayorov,A.V.et al.,,2008,J.Med.Chem.51:187-195。对于Hyp(Bzl),t-丁基甘氨酸和MAMB-见Grieco,P.,et al.,2007,Peptides 28:1191-1196。对于Azt,Pip,Nip,Tic,Oic-见Bednarek,M.A.,2007,Chem.Biol.DrugDesign,69:350-355。对于内酰胺环化-见Mayorov,A.V,.et al.,2006,J.Med.Chem.49:1946-1952。对于Pen和Aib-见Balse-Srinivasan.P.,et al.,2003 J.Med.Chem,46:4965-4973。对于n-戊酰基和n-己酰基-见Cheung A.W.-H.,et al.,2003,Bio-organic&Med.Chem.Lett.,13:1307-1311。ORN(鸟氨酸)和homoArg-见Holder,J.R.et al.,2003,Peptides,24:73-82。对于Phg-见Holder,J.R.et al.,2002,J.Med.Chem.,45,3073-3081。对于2,3二氨基丙酸-见2004,Vig,B.S.,et al.,J.Med.Chem.,47(2):446-455。
【使用本发明的黑皮质素配体检定心血管效应】
有许多直接和间接检定本发明的黑皮质素配体的降解和心血管效应的本领域技术人员会知道,显而易见或可利用的可能的方法。
使用本发明的黑皮质素配体检定急性和慢性心血管测试,以便测定是否本文所述的C-端延伸可保护RF-药效团免于暴露。以此方式,间接,但以治疗可应用的方式测量C-端降解抗性。此外,用急性和慢性心血管测量,将黑皮质素配体导入/施用到人或哺乳动物后,及直到黑皮质素配体自人或哺乳动物身体血流清除,则知道心血管效应。急性心血管记录允许经数小时时期的这些药物作用的连续分析,允许配体施用后效应的密集观察。急性心血管测试的心血管参数包括:直接动脉压力组分(心脏收缩,心脏舒张,平均动脉压力,及心律)和EKG。经Millar固体状态压力变换器在股动脉中测量动脉压力组分。此允许任何动脉压力/心律异常的更精确的评估。自Millar变换器的信号在跨音速动脉压力模块中放大,然后发送到计算机运行EMKA软件(EMKA Technologies,Inc.,Falls Church,VA)。一般逐秒测量动脉压力组分信号,尽管毫秒或逐搏分析是替代性的测量。后来的分析可回顾地进行,经实验回放。起初,待分析的动脉压力组分包括峰MAP(平均动脉压力)和HR(心律)应答,及各相应曲线下面积。因为暴露了RF药效团的黑皮质素类似物产生延长及可变压力和心动加速作用,计算各曲线下面积(AUC)(见,例如,D′Angelo et al.,2005,Am.J.Physiol.Heart Circ.Physiol.,288(4):H1829-H1835),如是描述各心血管参数曲线的方程的第1和第2导数。对于慢性心血管测试,遥测系统允许经长时间(数天或周)监控多动物。各动物仅记录数秒(例如,5~10s)/分钟,以最大化电池生命及允许监控多动物。但是,现在较新模型允许无线再充电移植的发射机。以下描述了用于慢性心血管测试的一种遥测模型。
遥测系统可用于用直接输入到运行EMKA ecgAuto-Cardio2+的计算机同时和连续监控。在此方法中,使用无菌过程将遥测发射机手术移植到大鼠腹腔。手术期间,将发射机的导管插入腹部主动脉及用组织粘合剂紧固。将遥测单元ECG电极皮下缝合到右上胸肌肉和左上部腹部壁肌肉。这些单元同时提供ECG和动脉压力信号。动物一般允许7~10天的手术恢复,使用动脉压力和HR的昼夜节律的返回作为目的度量。对于急性实验,将股IV线隧通到上背部,取出及存储在钢钮组件之内,缝合到动物的背部。发射机会使用铅II构型产生动脉压力信号(经插导管的腹部主动脉)和ECG信号。对此,将铅移植在胸的右上部象限的肌肉组织下,及左上部腹部区的肌肉组织之内。这些过程良好描述于文献(Stieber等人,2006,Mol.Pharmacol.,69(4):1328-37),以及制造商的流程。
对于黑皮质素配体慢性施用到大鼠模型,使用用于IV输注的Alza微型泵及持续的释放颗粒(Strader,A.D.,et al.,2007,J.Pharmacol.Exp.Ther.,322(3):1153-1161;and Innovative Research of America,Sarasota,FL)。本发明的黑皮质素配体的开始有效每天剂量是1mg/kg/天持续14天,及滴定达10mg/kg/天。作为在微型泵中药物降解的对照,运行并行温育的(37℃)对照及通过高效液相层析(HPLC)评定任何肽破断。
施用方法包括注射,口腔,鼻和粘膜施用。如果通过注射施用,注射可为静脉内,皮下,肌内,腹膜内或其他本领域知道的手段。本发明的黑皮质素配体可通过任何本领域知道的手段配制,包括但不限制于作为片剂,胶囊,小胶囊,悬浮液,粉剂,冻干制剂,栓剂,目镜滴,皮肤贴剂,口腔可溶性制剂,喷雾剂,气雾剂等的制剂,及可与缓冲剂,结合剂,赋形剂,稳定剂,抗氧化剂和本领域知道的其他剂混合及配制。鼻施用包括本发明的黑皮质素配体的任何形式的鼻内施用。本发明的黑皮质素配体可在水溶液,诸如包括盐水,柠檬酸盐或其他常见的赋形剂或防腐剂的溶液中。黑皮质素配体也可为干,粉或冻干制剂。
当用本发明的不同黑皮质素配体施用时,减少的心血管效应(血压和心律失常)在人或动物中相对。当比较本发明的具有C-端延伸的黑皮质素配体对比其无C-端延伸的对应物之间时,其相对减少。
包含本发明的黑皮质素配体的药物组合物和/或试剂盒用于调控及治疗跨重量调节(例如,肥胖症,厌食症和恶病质),激素分泌,外分泌腺分泌过多,免疫-关联病情和性功能障碍的许多病情。
【应用】
跨激素,神经元,酶促和其他细胞外和细胞内机理的本发明的黑皮质素配体的生理学调控效应还影响身体情况诸如重量调节(例如,肥胖症,厌食症和恶病质),激素分泌(例如,干眼和/或干口综合征),以及免疫-关联病情和性功能障碍。许多这些生理学机理的功能障碍导致疾病。在本申请中,生理学调控效应可区分及不同于心血管效应。
在一实施方式中,本发明的黑皮质素配体的生理学调控效应致使使用激动剂黑皮质素类似物(al-Obeidi et al.,J.Med Chem,1989,32(12),2555-2561)。在另一实施方式中,生理学调控效应致使使用拮抗剂黑皮质素类似物(Hruby et al.,1995,J.Med.Chem.,38:3454-3461;Jayawickreme et al.,1994,J.Biol.Chem.,269:29846-29854)。
总之,提供非-天然存在的黑皮质素配体,包括偶联于耐降解的C-端延伸(及任选地,N-端延伸),以产生具有减小的或消除的心血管活性而保留期望的黑皮质素调控活性的稳定的黑皮质素配体的黑皮质素类似物。
将本申请引用的全部参考文献,特别是针对合成方法的全部参考文献如在本文明确地引用地整体并入本文。
Claims (17)
1.非-天然存在的黑皮质素配体,其包含偶联于耐降解的C-端延伸的黑皮质素类似物。
2.权利要求1的非-天然存在的黑皮质素配体,其中耐降解的C-端延伸选自:至少1种氨基酸,至少1种修饰的氨基酸,肽模拟物,及其组合。
3.权利要求1的非-天然存在的黑皮质素配体,其中耐降解的C-端延伸选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮-环。
4.权利要求3的非-天然存在的黑皮质素配体,其还包含N-端延伸。
5.权利要求1的非-天然存在的黑皮质素配体,其如式I所示:
Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-X1-X2-X3(式I)
其中:
各R1~R7独立地是氨基酸或肽模拟物;
Y1缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸和L-脯氨酸;
Y2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;
Y3缺失或选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;
X1选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸和L-脯氨酸和哌嗪-2-酮环;
X2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;以及
X3缺失或选自:D-苏氨酸,L-苏氨酸和哌嗪-2-酮环。
6.权利要求5的非-天然存在的黑皮质素配体,其中:
R1缺失或选自:半胱氨酸,正亮氨酸,乙酰化的正亮氨酸,乙酰化的半胱氨酸,D-苯丙氨酸,乙酰化的D-苯丙氨酸,琥珀酸,o-酞酸,酪氨酸,天冬氨酸,戊二酸,CO-顺式-CH=CH-CO,n-戊酰基,及n-己酰基;
R2缺失或选自:脯氨酸,天冬氨酸,谷氨酸,甘氨酸,半胱氨酸,正亮氨酸,精氨酸,琥珀酸,戊二酸,CO-顺式-CH=CH-CO,n-戊酰基,及n-己酰基;
R3选自:组氨酸,在第1或3位甲基化的组氨酸,D-脯氨酸,L-脯氨酸,D-Nal(2′),L-Nal(2′),琥珀酸,tButGly,Hyp(Bzl),Mamb,Oic,正亮氨酸,Aba,β-丙氨酸,及Tic;
R4选自:组氨酸,D-苯丙氨酸,L-苯丙氨酸,D-Nal(2′),pCl-D-Phe和(o-Phe)Phe;
R5选自:精氨酸,高精氨酸,鸟氨酸,丙氨酸,脯氨酸,Pip,Nip,Tic,Phg,Sar和Azt;
R6选自:D-色氨酸,L-色氨酸,D-Nal(2′),L-Nal(2′),Tic和Bip;
R7缺失或选自:甘氨酸,谷氨酸,半胱氨酸,赖氨酸和2,3-二氨基-丙酸;
其中如果R3是Aba,则R4选自:D-Phe,D-Nal(2′)和pCl-D-Phe;以及
其中如果R2是n-戊酰基或n-己酰基,则R1,Y1,Y2和Y3缺失。
7.权利要求6的非-天然存在的黑皮质素配体,其中黑皮质素配体被环化。
8.权利要求7的非-天然存在的黑皮质素配体,其中黑皮质素配体通过选自下列的部分被环化:
当R1或R2是半胱氨酸,且R7或X1是半胱氨酸时,R1或R2和R7或X1之间的二硫键;
当R1是正亮氨酸,且R7是谷氨酸时,R1和R7之间的内酰胺桥;
当R2是谷氨酸或天冬氨酸,且R7是赖氨酸时,R2和R7之间的侧链内酰胺桥;
当R1是琥珀酸或o-酞酸,且R7是赖氨酸时,R1和R7之间的内酰胺闭合;以及
当R2或R3是琥珀酸,且R7是2,3-二氨基-丙酸时,R2或R3和R7之间的内酰胺闭合。
9.权利要求8的非-天然存在的黑皮质素配体,其中当X1是半胱氨酸时,X2不缺失。
10.权利要求1的非-天然存在的黑皮质素配体,其如式II所示:
Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-R8-R9-X1-X2-X3(式II)
其中:
各R1~R9独立地是氨基酸或肽模拟物;
Y1缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸和L-脯氨酸;
Y2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;
Y3缺失或选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸和哌嗪-2-酮环;
X1选自:半胱氨酸,D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;
X2缺失或选自:D-苏氨酸,L-苏氨酸,D-脯氨酸,L-脯氨酸,及哌嗪-2-酮环;以及
X3缺失或选自:D-苏氨酸,L-苏氨酸,及哌嗪-2-酮环。
11.权利要求10的非-天然存在的黑皮质素配体,其中:
R1是酪氨酸;
R2是缬氨酸;
R3选自:甲硫氨酸,正亮氨酸,半胱氨酸和L-青霉胺;
R4选自:甘氨酸,D-半胱氨酸,L-半胱氨酸,天冬氨酸,及正亮氨酸;
R5选自:组氨酸,正亮氨酸,脯氨酸和Aib;
R6选自:苯丙氨酸,D-Nal(2′)和L-Nal(2′);
R7是精氨酸;
R8选自:色氨酸和D-Nal(2′);以及
R9缺失或选自:天冬氨酸,半胱氨酸,青霉胺和赖氨酸。
12.权利要求11的非-天然存在的黑皮质素配体,其中黑皮质素配体被环化。
13.权利要求12的非-天然存在的黑皮质素配体,其中当R4是天冬氨酸和R9是赖氨酸时,黑皮质素配体通过R4和R9之间的内酰胺侧链被环化。
14.权利要求6的非-天然存在的黑皮质素配体,其中黑皮质素类似物是MC4受体激动剂,MC4受体拮抗剂,MC3受体激动剂,MC3受体拮抗剂,和/或MC5激动剂。
15.权利要求11的非-天然存在的黑皮质素配体,其中黑皮质素类似物是MC3拮抗剂。
16.权利要求6的非-天然存在的黑皮质素配体,其中当R4是D-苯丙氨酸时,D-苯丙氨酸在对位被卤化。
17.药物组合物,其包含权利要求1的非-天然存在的黑皮质素配体和药学盐。
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