CN118271400A - 肽组合物 - Google Patents
肽组合物 Download PDFInfo
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- CN118271400A CN118271400A CN202410043113.3A CN202410043113A CN118271400A CN 118271400 A CN118271400 A CN 118271400A CN 202410043113 A CN202410043113 A CN 202410043113A CN 118271400 A CN118271400 A CN 118271400A
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- phe
- arg
- cys
- trp
- cyclo
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Abstract
本发明涉及为黑皮质素‑4受体(MC4R)调节剂(例如激动剂和拮抗剂)的多肽化合物和包含它们的药物组合物。本文所述的化合物为如下结构式(I)的多肽:或其药学上可接受的盐。结构式(I)中的变量的值和优选值如本文所述。
Description
本申请为申请日2014年3月14日,发明名称为“肽组合物”的中国申请201480026843.7的分案申请。
相关申请
本申请要求2013年3月15日提交的美国临时申请号61/790,469的权益。将上述申请的全部教导引入本文作为参考。
发明背景
诸如肥胖、代谢综合征、胰岛素抵抗和糖尿病这样的障碍显著地添加到卫生保健费用中且可以对患病的个体、其家庭和医疗护理提供者的生活质量具有严重影响。这些障碍的发生率正在增加,接近了流行病比例。因此,对于治疗这些障碍的组合物和方法存在需求。
发明概述
本发明涉及为黑皮质素-4受体(MC4R)调节剂的多肽化合物和包含它们的药物组合物。
在一个具体的实施方案中,所述多肽化合物是具有如下结构式(I)的分离的多肽:
或其药学上可接受的盐,
其中:
R1是H或C1-C6酰基;
R2是-NR3R4或-OR5,其中R3、R4和R5各自独立地是H或C1-C6烷基;
A1是选自Arg、Lys、Orn、His、Nle、Phe、Val、Leu、Trp、Tyr、Ala、Ser、Thr、Gln、Asn、Asp、Glu或TzAla的氨基酸;或
A1是选自如下的部分:任选取代的C1-C12烷基、任选取代的C6-C18芳基、任选取代的C5-C18杂芳基、芳烷基,其中所述芳基部分是任选取代的C6-C18芳基,且所述烷基部分是任选取代的C1-C12烷基或杂芳烷基,其中所述杂芳基部分是任选取代的C5-C18杂芳基,且所述烷基部分是任选取代的C1-C12烷基;
A2和A8各自独立地是选自Cys、hCys、Pen、Asp、Glu、Lys、Orn、Dbu或Dpr的氨基酸,其中A2和A8配对选择以便能够在其相应的侧链之间形成共价键;
A3不存在或是选自Ala、Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn、Aib或残基Y的氨基酸,其中Y是选自由如下结构式表示的氨基酸的氨基酸:
其中:
R11和R12各自独立地是H、-CH3、苯基或苄基;
R21、R22、R23和R24各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
R31、R32、R33、R34、R41、R42和R43各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
A4不存在或是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、任选取代的His、Trp、Tyr、Lys、Arg、sChp的氨基酸残基,或残基X,其中X是选自由如下结构式表示的氨基酸的氨基酸:
其中:
R51和R52各自独立地是H、-CH3、苯基或苄基;
R61、R62、R63和R64各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
R71、R72、R73、R74、R81、R82和R83各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
A5是任选取代的Phe、任选取代的1-Nal或任选取代的2-Nal;
A6是Arg;且
A7是Trp,
其中任意的氨基酸残基是L-或D-构型,
条件是:
1)A3和A4不是都不存在;
2)当A4是氨基酸时,A3不是Aib或Gly;和
3)当A4是His且A5是D-Phe或2-Nal时,A3不是D-氨基酸或L-Ala;
4)当A2和A8各自选自Cys、hCys或Pen时,则:
(a)当A4不存在时,则A3不是L-His;
(b)当A3不存在时,则A4不是L-His;和
(c)当A4是His时,则A3不是Glu、Leu或Lys。
本发明还涉及治疗需要治疗的个体的响应于MC4R调节的障碍的方法。该方法包括对所述个体施用有效量的本文所述的MC4R调节剂。在一个具体的实施方案中,响应于MC4R调节的障碍包括1型糖尿病、2型糖尿病、肥胖、胰岛素抵抗、代谢综合征、男性勃起功能障碍、女性性功能障碍、非酒精性脂肪肝病、非酒精性脂肪性肝炎、包括酒精中毒性进食障碍的物质滥用障碍、恶病质、炎症和焦虑。
在一些实施方案中,本发明的化合物和组合物对MC4R和黑皮质素-3受体(MC3R)比对黑皮质素-1受体(MC1R)具有更高的选择性和效能。本发明的化合物和组合物可以减少或消除不期望的副作用,例如血压效应增加、心率增加、对性唤起的不期望的作用和皮肤色素沉着增加。
发明详述
本发明实施例实施方案的描述如下。
词汇表
用于定义肽类的命名法是典型地本领域中使用的,其中N-末端上的氨基显示在左侧,而C-末端上的羧基显示在右侧。
本文所用的术语“氨基酸”包括天然存在的氨基酸和非天然的氨基酸。除非另有指示,否则本文所述化合物上的所有氨基酸及其残基均可以为D或L构型。
用于实施本文所述方法的本发明化合物可以具有一个或多个手性中心且由此以许多立体异构体形式存在。本发明范围内包括所有立体异构体及其混合物。可以使用制备型HPLC和柱与手性固定相分离外消旋化合物或使用本领域技术人员公知的方法将其拆分成各对映体。此外,可以拆分手性中间体化合物并且用于制备本发明的手性化合物。
本文所述的化合物可以以一种或多种互变体形式存在。所有互变体及其混合物都包括在本发明范围内。
除非另有定义,否则本文所用的所有技术和科学术语具有与本发明所属技术领域普通技术人员通常所理解的相同的含义。将本文举出的所有出版物、专利申请、专利和其它参考文献完整地引入本文作为参考。
除非另有指示,否则本公开文本中氨基酸的所有缩写(例如Ala)是指氨基酸残基,即表示-NH-C(R)(R′)-CO-的结构,其中R和R′各自独立地是氢或氨基酸侧链(例如对于Ala,R═CH3,且R′═H;或R和R′可以连接成环系)。
多肽末端上的命名“Ac”或“NH2”表示相应的末端分别被酰化或酰胺化。
短语“氨基酸侧链之间的共价键”是指所述两个氨基酸残基的侧链各自包括能够彼此形成共价键的官能团。这种键的实例包括Cys、hCys或Pen侧链形成的二硫键和一个氨基酸侧链的氨基和另一个氨基酸侧链的羧基形成的酰胺键,例如Asp、Glu、Lys、Orn、Dbu或Dpr。在实施例实施方案中,氨基酸可以配对选择以便能够在其相应的侧链之间形成共价键。当在氨基酸侧链之间形成共价键时,多肽可以被环化。这类环多肽可以用一种结构式表示或通过缩略语符号“c()”或“环()”表示。例如,“-c(Cys-Cys)-”或“-环(Cys-Cys)-”表示如下结构:
而“-c(Asp-Lys)-”或“-环(Asp-Lys)-”表示如下结构:
单独的或作为较大部分例如“羟基烷基”、“烷氧基烷基”、“烷基胺”的组成部分的“烷基”是指具有指定碳原子数、典型地具有1-12个碳原子的直链或支链饱和脂族基团。更具体地,所述脂族基团可以具有1-8、1-6或1-4个碳原子。该术语以如下基团为示例,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基等。
“卤代烷基”是指被一个或多个卤原子取代的烷基。
“卤素”和“卤代”是指氟、氯、溴或碘。
“氰基”是指基团-CN。
“Ph”是指苯基。
“羰基”是指二价-C(O)-基团。
单独的或作为如“芳烷基”中的较大部分的组成部分的“芳基”是指具有单环或多个稠合环的6-18个碳原子的芳族碳环基团。术语“芳基”还包括与环烷基或杂环烷基稠合的芳族碳环。芳基的实例包括苯基、苯并[d][1,3]间二氧杂环戊烯、萘基、菲基等。
“芳氧基”是指vOAr基团,其中O是氧原子,且Ar是如上述所定义的芳基。
“芳烷基”是指具有至少一个被芳基部分例如苄基、-(CH2)2苯基、-(CH2)3苯基、-CH(苯基)2等替代的烷基氢原子的烷基。
单独的或作为如“杂芳烷基”中的较大部分的组成部分的“杂芳基”是指5-18元单环、双环或三环杂芳族环系,其包含1-4个独立地选自氮、氧和硫的杂原子。术语“杂芳基”还包括与环烷基或杂环烷基稠合的杂芳族环。杂芳基的具体实例包括任选取代的吡啶基、吡咯基、嘧啶基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、1,3,4-三嗪基、1,2,3-三嗪基、苯并呋喃基、[2,3-二氢]苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并三唑基、异苯并噻吩基、吲哚基、异吲哚基、3H-吲哚基、苯并咪唑基、咪唑并[1,2-a]吡啶基、苯并噻唑基、苯并噁唑基、喹嗪基、喹唑啉基、酞嗪基(pthalazinyl)、喹喔啉基(quinoxalinyl)、噌啉基、萘啶基、吡啶并[3,4-b]吡啶基、吡啶并[3,2-b]吡啶基、吡啶并[4,3-b]吡啶基、喹啉基、异喹啉基、四唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、嘌呤基、蝶啶基、咔唑基、呫吨基、苯并喹啉基等。
“杂芳烷基”是指具有至少一个被杂芳基部分例如-CH2-吡啶基、-CH2-嘧啶基等替代的烷基氢原子的烷基。
“烷氧基”是指基团-O-R,其中R是“烷基”、“环烷基”、“链烯基”或“炔基”。烷氧基的实例包括,例如甲氧基、乙氧基、乙烯氧基等。
“羟基烷基”和“烷氧基烷基”是分别被羟基和烷氧基取代的烷基。
“氨基”是指-NH2;“烷基胺”和“二烷基胺”分别是指-NHR和-NR2,其中R是烷基。“环烷基胺”和“二环烷基胺”分别是指-NHR和-NR2,其中R是环烷基。“环烷基烷基胺”是指-NHR,其中R是环烷基烷基。“[环烷基烷基][烷基]胺”是指-N(R)2,其中一个R是环烷基烷基,而另一个R是烷基。
“酰基”是指R″-C(O)-,其中R″是H、烷基、取代的烷基、杂烷基、取代的杂烷基、链烯基、取代的链烯基、芳基、烷基芳基或取代的烷基芳基,且在一个具体的实施方案的通式中显示为“Ac”。
“烷基”、“芳基”或“杂芳基”等的适合的取代基是形成本发明稳定的化合物的那些。适合的取代基的实例是选自如下的那些:卤素、-CN、-OH、-NH2、(C1-C4)烷基、(C1-C4)卤代烷基、芳基、杂芳基、(C3-C7)环烷基、(5-7元)杂环烷基、-NH(C1-C6)烷基、-N((C1-C6)烷基)2、(C1-C6)烷氧基、(C1-C6)烷氧基羰基、-CONH2、-OCONH2、-NHCONH2、-N(C1-C6)烷基CONH2、-N(C1-C6)烷基CONH(C1-C6)烷基、-NHCONH(C1-C6)烷基、-NHCON((C1-C6)烷基)2、-N(C1-C6)烷基CON((C1-C6)烷基)2、-NHC(S)NH2、-N(C1-C6)烷基C(S)NH2、-N(C1-C6)烷基C(S)NH(C1-C6)烷基、-NHC(S)NH(C1-C6)烷基、-NHC(S)N((C1-C6)烷基)2、-N(C1-C6)烷基C(S)N((C1-C6)烷基)2、-CONH(C1-C6)烷基、-OCONH(C1-C6)烷基-CON((C1-C6)烷基)2、-C(S)(C1-C6)烷基、-S(O)p(C1-C6)烷基、-S(O)pNH2、-S(O)pNH(C1-C6)烷基、-S(O)pN((C1-C6)烷基)2、-CO(C1-C6)烷基、-OCO(C1-C6)烷基、-C(O)O(C1-C6)烷基、-OC(O)O(C1-C6)烷基、-C(O)H或-CO2H。更具体地,所述取代基选自卤素、-CN、-OH、-NH2、(C1-C4)烷基、(C1-C4)卤代烷基、(C1-C4)烷氧基、苯基和(C3-C7)环烷基。在本发明范围内,所述"取代"还是指包括其中氢原子被氘原子替代的情况。p是具有1或2的值的整数。
取代的Phe上的适合的取代基包括任意芳族碳上的1-5个取代基,所述取代基选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2或-OCH3。实例包括Phe(2’-F)、Phe(2’-Cl)、Phe(2’-Br)、Phe(2’-I)、Phe(2’-CN)、Phe(2’-CH3)、Phe(2’-OCH3)、Phe(2’-CF3)、Phe(2’-NO2)、Phe(3’-F)、Phe(3’-Cl)、Phe(3’-Br)、Phe(3’-I)、Phe(3’-CN)、Phe(3’-CH3)、Phe(3’-OCH3-)、Phe(3’-CF3)、Phe(3’-NO2)、Phe(4’-F)、Phe(4’-Cl)、Phe(4’-Br)、Phe(4’-I)、Phe(4’-CN)、Phe(4’-CH3)、Phe(4’-OCH3)、Phe(4’-CF3)、Phe(4’-NO2)、Phe(4’-t-Bu)、Phe(2’,4’-二F)、Phe(2’,4’-二Cl)、Phe(2’,4’-二Br)、Phe(2’,4’-二I)、Phe(2’,4’-二-CN)、Phe(2’,4’-二-CH3)、Phe(2’,4’-二-OCH3)、Phe(3’,4’-二F)、Phe(3’,4’-二Cl)、Phe(3’,4’-二Br)、Phe(3’,4’-二I)、Phe(3’,4’-二-CN)、Phe(3’,4’-二-CH3)、Phe(3’,4’-二-OCH3)、Phe(3’,5’-二F)、Phe(3’,5’-二Cl)、Phe(3’,5’-二Br)、Phe(3’,5’-二I)、Phe(3’,5’-二-CN)、Phe(3’,5’-二CH3)、Phe(3’,5’-二-OCH3)或Phe(3’,4’,5’-三F)。
取代的His上的适合的取代基包括任意可取代环原子上的1-3个取代基,所述取代基选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2、苄基或-OCH3。实例包括1-甲基-组氨酸和3-甲基-组氨酸。
命名“(氨基酸)n”是指重复n次的氨基酸。例如,命名“(Pro)2”或“(Arg)3”是指分别重复2次或3次的脯氨酸或精氨酸。
本文公开的多肽化合物的药学上可接受的盐包括在本发明内。例如,可以通过使所述化合物与适合的有机酸或无机酸反应得到包含胺或其它碱性基团的化合物的酸式盐,得到药学上可接受的阴离子盐形式。阴离子盐的实例包括乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、乙二胺四乙酸钙、右旋樟脑磺酸、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、乙二胺四乙酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐(glyceptate)、葡糖酸盐、谷氨酸盐、乙二醇基对氨基苯胂酸盐(glycollylarsanilate)、己基间苯二酚酸盐(hexylresorcinate)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、扑酸盐、泛酸盐、磷酸盐/二磷酸盐(diphospate)、聚半乳糖酸盐、水杨酸盐、硬脂酸盐、次醋酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙基碘和三氟乙酸盐。
可以通过与适合的碱反应制备包含酸性官能团的化合物的盐。可以使用得到药学上可接受的阳离子的碱制备这种药学上可接受的盐,包括碱金属盐(尤其是钠和钾)、碱土金属盐(尤其是钙和镁)、铝盐和铵盐,以及由生理学可接受的碱形成的盐,例如三甲胺、三乙胺、吗啉、吡啶、哌啶、甲基吡啶、二环己胺、N,N’-二苄基乙二胺、2-羟基乙胺、双-(2-羟基乙基)胺、三-(2-羟基乙基)胺、普鲁卡因、二苄基哌啶、去氢枞胺、N,N’-双去氢枞胺、葡萄糖胺、N-甲基葡萄糖胺、可力丁、奎宁、喹啉和碱性氨基酸,例如赖氨酸和精氨酸。
可以将所公开的化合物与作为药物组合物的组成部分的可接受的药用载体一起施用于个体。所施用的化合物制剂可以根据所选择的施用途经(例如溶液、乳剂、胶囊)的不同而改变。适合的药用载体可以包含不与所述化合物发生相互作用的惰性成分。可以使用标准药物制剂技术,例如Remington's Pharmaceutical Sciences,MackPublishingCompany,Easton,PA中所述的那些。用于胃肠外施用的适合的药用载体包括,例如无菌水、生理盐水、抑菌盐水(包含约0.9%mg/ml苄醇的盐水)、磷酸缓冲盐水、Hank溶液、林格液-乳酸盐等。用于包囊组合物(例如硬胶囊涂层或环糊精(cyclodextrasn)中)的方法是本领域公知的(Baker,等人,"Controlled Release of Biological Active Agents",John Wiley和Sons,1986)。
本文所用的短语“响应于黑皮质素-4受体调节的障碍”是指可以通过活化(激动)或抑制MC4R治疗的任意障碍。这类障碍的实例在下文中详细描述。
本文所用的术语“调节剂”是指与靶受体发生相互作用并且影响其生物功能的化合物。调节剂的实例包括全激动剂、部分激动剂、中性拮抗剂和反激动剂。
本文所用的术语“激动剂”是指天然存在的或合成的在与其本文的靶标MC4R发生相互作用(例如与之结合)时将MC4R的信号传导活性升至高于其基础水平的任意化学化合物。激动剂可以是超兴奋剂(即能够产生大于靶受体的内源性激动剂的最大响应且由此具有100%以上效能的化合物)、全激动剂(即在受体占据和活化之后引起最大响应的化合物)或部分激动剂(即可以活化受体、但不能引起受体系统的最大响应的化合物)。MC4R激动剂的实例如在下文中详细描述。
本文所用的术语“拮抗剂”是指在与其本文的靶标MC4R发生相互作用(例如与之结合)时以剂量依赖性方式阻断激动剂化合物与MC4R的信号传导活性的任意化学化合物。
本文所用的术语“反激动剂”是指在与其本文的靶标MC4R发生相互作用(例如与之结合)时以剂量依赖性方式降低MC4R的信号传导活性的基础水平的任意化学化合物。
本文所用的“有效量”是指以治疗或预防方式足以治疗目标障碍的治疗剂或治疗剂组合的用量。有效量的实例典型地约为0.0001mg/kg体重-约500mg/kg体重。实例范围约为0.0001mg/kg体重-约500mg/kg。例如,有效量可以约为0.005mg/kg-约500mg/kg。在其它实例中,该范围约为0.0001mg/kg-约5mg/kg。在其它实例中,有效量约为0.01mg/kg体重-50mg/kg体重或0.01mg/kg体重-20mg/kg体重。
本文所用的术语“个体”是指哺乳动物,优选人,还可以是指需要兽医治疗的动物,例如陪伴动物(例如狗、猫等)、农场动物(例如牛、绵羊、猪、马等)和实验室动物(例如大鼠、小鼠、豚鼠等)。
本文所用的术语“第二种活性剂”包括任意活性药物成分(API),在与本文所述的肽组合时,其增强由单独的本文所述的肽产生的治疗作用或显示与本文所述的肽的协同作用(即显示大于累加作用的联合作用)。本文所用的“增强的治疗作用”包括非协同作用的改善的治疗特性。增强的治疗作用的实例包括降低的本文所述的肽的有效剂量、本文所述的肽的延长的治疗窗等。可以施用一种或多种第二种活性剂。第二种活性剂的实例在下文中详细描述。
可以在本文所述的肽施用之前、与之同时或之后施用第二种活性剂。因此,可以将本文所述的肽和第二种活性剂在单一制剂中一起施用或可以将它们在单独的制剂中例如同时或依次施用。例如,如果本文所述的肽和第二种活性剂在单独的组合物中依次施用,则可以将本文所述的肽在第二种治疗剂之前或之后施用。此外,可以将本文所述的肽和第二种活性剂使用类似的给药方案施用。例如,本文所述的肽和第二种治疗剂可以具有不同的半衰期和/或以不同的时间期限起作用,使得将本文所述的肽以比第二种治疗剂更大的频率施用,或反之亦然。最终,可以在本文所述的肽之后施用第二种活性剂,作为连续应用两种治疗剂的结果,可以进一步增强治疗效能。可以将本文所述的肽或第二种活性剂紧急地或长期施用。
可以通过共同施用第一种用量的具有MC4R调节剂活性的化合物或其药学上可接受的盐和第二种用量的至少一种第二种活性剂实现本发明方法或组合物中的有效量。在一个实施方案中,可以以相应的有效量各自施用本文所述的肽和第二种活性剂(即如果单独施用可以为治疗有效各自用量)。在另一个实施方案中,以单独不提供治疗作用的用量(亚治疗剂量)各自施用本文所述的肽和第二种活性剂。在另一个实施方案中,可以以有效量施用本文所述的肽,而以亚治疗剂量施用第二种活性剂。在另一个实施方案中,可以以亚治疗剂量施用本文所述的肽,而以有效量施用第二种活性剂。在实施例实施方案中,本文所述的肽和第二种活性剂的组合显示比单独的本文所述的肽或第二种活性剂增强的治疗作用或协同作用。
可以使用用于评价药物相互作用的适合的方法确定协同作用的存在。适合的方法包括,例如Sigmoid-Emax方程(Holford,N.H.G.和Scheiner,L.B.,Clin.Pharmacokinet.6:429-453(1981))、Loewe加和性方程(Loewe,S.和Muischnek,H.,Arch.Exp.Pathol.Pharmacol.114:313-326(1926))和中间-效应方程(Chou,T.C.和Talalay,P.,Adv.Enzyme Regul.22:27-55(1984))。上文涉及的每个方程可以配有实验数据,生成相应的示意图,以辅助评价药物组合的作用。与上文涉及的方程相关的相应示意图分别是浓度-效应曲线、等效线图解曲线和联合指数曲线。
本文所用的“治疗”包括部分或基本上实现延迟、抑制或预防与目标障碍相关的临床适应征的发展。例如,“治疗”包括部分或基本上实现如下结果的一种或多种:部分或完全减轻体重(例如,正如根据人体质量指数BMI所确定的);改善或改进与肥胖相关的临床症状或指征,例如II型糖尿病、前驱糖尿病病症、血红蛋白A1C(Hb1Ac)的血液水平高于6%、高胰岛素血症(hyperinsulimenia)、高脂血症、胰岛素无敏感性、葡糖耐受不良等;延迟、抑制或预防肥胖和肥胖相关适应征发展;或部分或完全延迟、抑制或预防肥胖或肥胖相关适应征发作或发展。延迟、抑制或预防肥胖发展包括,例如延迟、抑制或预防具有正常体重的个体发展成肥胖。术语“治疗”还包括部分或完全降低冠状动脉疾病、中风和与代谢综合征相关的糖尿病(例如2型)的风险和改善或改进与代谢综合征相关的代谢综合征的临床症状或征兆,例如上述五种指征的任意一种或多种。例如,“治疗”包括延迟、抑制或预防与代谢综合征包括胰岛素抵抗、葡萄糖清除相关的参数和心血管疾病参数包括心率和血压发展,关节病、炎症、睡眠呼吸暂停、贪食症和其它进食障碍,包括食欲亢进、用于体重减轻的支持疗法和矫形外科前的支持型体重减轻疗法。“预防性治疗”是指在目标障碍的临床症状发作前的治疗以预防、抑制或降低其发生率。
响应于MC4R调节的障碍
响应于MC4R调节的障碍的实例包括急性和慢性炎症疾病,诸如泛发性炎症、炎性肠病、脑炎症、脓毒症和脓毒性休克;具有自身免疫成分的疾病,例如类风湿性关节炎、痛风性关节炎和多发性硬化;代谢疾病和伴有体重增长的医学病症,例如肥胖、进食障碍和帕-魏二氏综合征;代谢疾病和伴随体重减轻的医学病症,例如食欲减退、食欲亢进、艾滋病消耗、恶病质、癌症恶病质和虚弱老人消瘦;糖尿病和糖尿病相关病症和糖尿病并发症,例如视网膜病变;瘤性增生,例如皮肤癌和前列腺癌;生殖或性医学病症,例如女性中的子宫内膜异位症和子宫出血、性功能障碍、勃起功能障碍和女性中的性反应减少;因治疗产生的疾病或病症或生物体创伤,例如器官移植排斥、局部缺血和再灌注损伤、脊髓损伤治疗和加速伤口愈合以及由化疗、放疗、短暂或永久性固定导致的体重减轻和透析;心血管疾病或病症,例如出血性休克、心源性休克、低血容量性休克、心血管疾患和心原性恶病质;肺部疾病或病症,例如急性呼吸窘迫综合征、慢性阻塞性肺疾病、哮喘和肺纤维化;增强免疫耐受性和抗击对免疫系统的攻击,例如与一些过敏原或器官移植排斥相关的那些;治疗皮肤病和病症,例如银屑病、皮肤色素沉着耗尽、痤疮、瘢痕疙瘩形成和皮肤癌;行为、中枢神经系统或神经元性病症和障碍,例如焦虑、抑郁症、记忆和记忆力功能障碍、调节疼痛感觉和治疗神经性疼痛;与饮酒、酒精滥用和/或酒精中毒相关的病症和疾病;和肾病症或疾病,例如治疗肾病性恶病质或钠尿增多。另外的实例包括个体的正常或稳态的活动,包括甲状腺素释放、醛固酮合成和释放、体温、血压、心率、血管紧张度、脑血流量、血糖水平、骨代谢、骨形成或发育、卵巢重量、胎盘形成、催乳素和FSH分泌、子宫内胎儿发育、分娩、精子发生、皮脂和信息素分泌、神经保护和神经生长和调节动机、学习和其它行为。其它实例包括贪食症、食欲亢进或其它进食障碍。
在实施例实施方案中,响应于MC4R受体调节的障碍是1型糖尿病、2型糖尿病、肥胖、胰岛素抵抗、代谢综合征、心血管疾病或低密度脂蛋白/高密度脂蛋白/甘油三酯失衡、非酒精性脂肪肝病和物质滥用障碍。
在实施例实施方案中,响应于MC4R受体调节的障碍是1型糖尿病、2型糖尿病、肥胖、胰岛素抵抗或代谢综合征。
肥胖
本文所用的术语“肥胖”是指具有约30kg/m2或更高的人体质量指数(BMI)的个体,例如BMI为25、26、27、28、29、30、31、32、33、34、35、36、37kg/m2或更高。在具体的实施方案中,肥胖个体具有被疾病控制中心(Center for Disease Control)定义为“肥胖”范围内的BMI。参见,在2011年10月28日最新评价的URL http://www.cdc.gov/obesity/defining.html。例如,在一些实施方案中,具有BMI>=30.0kg/m2的成年人属于肥胖。
糖尿病和相关障碍
在实施例实施方案中,用本发明提供的方法治疗的个体具有发生糖尿病相关障碍或处于增加的发生糖尿病相关障碍的风险中。“糖尿病相关障碍”是指糖尿病(包括1型(OMIM 222100)和2型(OMIM 125853))、胰岛素抵抗和代谢综合征。
在实施例实施方案中,待治疗的个体具有糖尿病(1型2型)、胰岛素抵抗或代谢综合征。在实施例实施方案中,所述障碍是糖尿病,例如2型糖尿病。在实施例实施方案中,所述个体具有发生如世界卫生组织(World Health Organization)和国际糖尿病联合会(International Diabetes Federation)在2006年公布的“Definition and diagnosis ofdiabetes mellitus and intermediate hyperglycaemia”所定义的2型糖尿病或处于增加的发生它的风险中,将这些文献完整地引入本文作为参考。在实施例实施方案中,糖尿病个体显示空腹血糖>=126mg/dL或2-小时血糖(口服施用75g葡萄糖后2小时)>=200mg/dL。在实施例实施方案中,糖尿病或前驱糖尿病显示糖化血红素水平升高,例如大于4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.8、6.0、6.2、6.4、6.6、6.8、7.0、7.2、7.4、7.6%或更高的总血红蛋白。在实施例实施方案中,糖尿病或前驱糖尿病可以根据遗传多态现象(包括,例如,导致表达水平改变的多态现象,例如升高或降低的表达水平和/或编码序列的变化)或接近如下表1中基因的一种或多种鉴定或进一步表征:
表1
在实施例实施方案中,可以用于鉴定或进一步表征用本发明提供的方法治疗的个体的另外的基因包括FTO(OMIM 610966)、JAZF1(OMIM 606246)和HHEX(OMIM 604420)。
在实施例实施方案中,可以用本发明提供的方法治疗的个体具有I型糖尿病。在实施例实施方案中,具有I型糖尿病的个体通过C-肽测定表征,例如禁食C-肽水平低于约1.0nmol/L,例如低于1.2、1.1、1.0、0.9、0.8、0.7、0.6、0.5、0.4nmol/L或更低,例如低于0.33、0.25、0.2或0.1nmol/L。在实施例实施方案中,在口服葡萄糖攻击后(口服施用75g葡萄糖后2小时)测定C-肽水平,并且检测到低于0.54nmol/L、例如低于0.50、0.45、0.40、0.35、0.30、0.25、0.20、0.15或0.10nmol/L的增加。空腹葡萄糖受损(110-125mg/dL)或葡萄糖耐量降低(75-g葡萄糖攻击后2-h:140-199mg/dL)可以用于鉴定或进一步表征具有1型糖尿病的个体的β细胞功能降低。在实施例实施方案中,根据存在针对胰岛细胞抗原和/或胰岛素的自身抗体鉴定或进一步表征1型糖尿病,例如定向于65kDa GAD(OMIM 138275)和/或磷酸酶相关IA-2分子的自身抗体。
胰岛素抵抗
在实施例实施方案中,所述障碍是“胰岛素抵抗”,其可以通过本领域公知的任意方式鉴定并且根据胰岛素降低血糖水平的能力下降表征。在实施例实施方案中,根据存在的如下基因的一种或多种中的一种或多种多态现象(包括,例如,导致表达水平改变的多态现象,例如升高或降低的表达水平和基因产物例如蛋白质的编码序列变体)鉴定或进一步表征胰岛素抵抗:RETN、PTPN1、TCF1(OMIM 142410;参见,例如多态现象0011)、PPP1R3A(OMIM 600917;参见,例如多态现象0001,0003)、PTPN1(OMIM 176885;参见,例如多态现象0001)、ENPP1(OMIM 173335;参见,例如多态现象0006)、IRS1(OMIM 147545;参见,例如多态现象0002)、EPHX2(OMIM 132811;参见,例如多态现象0001)、瘦素(OMIM 164160,参见,例如多态现象0001和0002)、瘦素受体(OMIM 601007,参见,例如多态现象0001,0002,0004和0005)或胰岛素受体(INSR、OMIM 147670,参见,例如多态现象0001-0037)。
代谢综合征
在实施例实施方案中,所述障碍是代谢综合征。本文所用的术语“代谢综合征”是指共同发生且增加冠状动脉疾病、中风和2型糖尿病的风险的一组症状。根据美国心脏协会和国家心脏、肺和血液研究院(American Heart Association and the National Heart,Lung and Blood Institute)),如果个体具有如下征兆的三种或三种以上,则存在代谢综合征,也称作X综合征:
1)血压等于或高于130/85mmHg;
2)空腹血糖(葡萄糖)等于或高于100mg/dL;
3)巨大腰围(围绕腰部的长度):
-男性-40英寸或以上;
-女性-35英寸或以上;
4)低HDL胆固醇:
-男性-40mg/dL以下;
-女性-50mg/dL以下;
5)甘油三酯类等于或高于150mg/dL。
代谢综合征可以通过测试个体的血压、血糖水平、HDL胆固醇水平、LDL胆固醇水平、总胆固醇水平和甘油三酯水平来诊断。
在实施例实施方案中,个体具有向心性肥胖(女性腰围>=80cm;亚洲男性>=90cm,包括南美和中美洲人种;和所有其他男性>=94cm)、BMI>30kg/m2、升高的甘油三酯(>=150mg/dL或用于这种脂质异常的特定治疗)、降低的HDL胆固醇(男性<40mg/dL,女性<50mg/dL 或用于这种脂质异常的特定治疗)、升高的血压(sBP>=130mmHg或dBP>=85mmHg或治疗预先诊断的高血压)或升高的空腹血糖(FPG>=100mg/dL或在先的2型糖尿病诊断),包括其组合。在实施例实施方案中,用本发明提供的方法治疗的个体具有代谢综合征或处于增加的其风险中,正如国际糖尿病联合会在2006年公布的“The IDF consensusworldwide definition of the metabolic syndrome”中所定义的,将该文献完整地引入本文作为参考,即个体具有向心性肥胖(如上所述和/或BMI>30kg/m2)和升高的甘油三酯、降低的HDL胆固醇、升高的血压或升高的空腹血糖的任意两种。在实施例实施方案中,根据个体存在的选自3q27(参见,例如OMIM 605552)和/或17p12(参见,例如OMIM 605572)的基因座上的突变表征或进一步表征代谢综合征。
MC4R突变导致的障碍
本发明涉及治疗患有MC4R对α-黑皮质素刺激激素(α-MSH)减弱的响应的个体的障碍的方法。该方法包括施用有效量的黑皮质素-4受体(MC4R)激动剂。在一个实施例实施方案中,所述个体是MC4R突变的杂合子携带者,导致MC4R对α-黑皮质素刺激激素(α-MSH)响应减弱。因为杂合子载体保留了对MC4R天然配体有响应的能力,所以通过施用MC4R激动剂治疗MC4R-相关障碍不依赖于MC4R突变类型的知识。
在一个实施例实施方案中,所述障碍是肥胖,例如MC4R-相关肥胖。在另一个实施例实施方案中,所述障碍是代谢综合征。
人MC4R基因(hMC4R)是由具有GenBank保藏号CH471077的基因组序列编码的充分表征的蛋白质。MC4R受体中的突变是严重儿童期肥胖的相关原因。已经注意到在青少年发作的肥胖人群中MC4R突变的携带者患病率约为2.5%,在严重肥胖儿童中的最高患病率为6%。具有MC4R突变的人显示大致上类似的表型,正如对于在具有MC4受体基因中的突变的小鼠描述的。那些人显示明确的摄食过度、超高胰岛素血症、脂肪量增加,伴随瘦体质、骨矿物质密度和直线性生长率,其中皮质醇水平、促性腺素、甲状腺和性类固醇水平不变。与MC4受体缺失相反,摄食过度和超高胰岛素血症倾向于人类个体中的年龄而减退。与MC4R敲除小鼠类似,杂合子携带者中的表型与纯合子携带者相比属于中间型的。在试验餐时观察到的显示出的摄食过度的严重性低于具有瘦素缺乏的人中观察到的水平。体外测定中观察到的MC4受体功能障碍的严重性预示由隐藏特定突变的个体在试验餐时摄入的食物量,并且与肥胖表型发作和严重性相关。至少90种不同的MC4受体突变与肥胖相关,且能够发现MC4受体中的另外的突变,它们导致类似的肥胖表型。
导致人肥胖的MC4R突变的实例描述在Farooqi等人,The Journal of ClinicalInvestigation,2000年7月,106卷(2),pp.271-279和Vaisse等人,The Journal ofClinical Investigation,2000年7月,106卷(2),pp.253-262中,将这些文献的相关部分引入本文作为参考。
可能导致人肥胖的另外的突变包括R18H、R18L、S36Y、P48S、V50M、F51L、E61K、I69T,D90N、S94R、G98R、I121T、A154D、Y157S、W174C、G181D、F202L、A219 V、I226T、G231S、G238D、N240S、C271R、S295P、P299L、E308K、I317V、L325F和750DelGA,如Xiang等人,“Pharmacological characterization of 30human melanocortin-4receptorpolymorphisms with the endogenous proopiomelanocortin-derived agonists,synthetic agonists and the endogenous agouti-related protein antagonist.”Biochemistry,2010Jun 8;49(22):4583-600中所述,将该文献的相关部分引入本文作为参考。
可能导致人肥胖的突变的另外的实例是在URL http://omim.org/entry/155541的Online Mendelian Inheritance in Man(OMIM),一个人基因和家族遗传疾病数据库,登记号为155541(MC4R)(更精确地,保藏号为155541.0001-155541.0023)中列出的那些。有代表性的实例包括4-BP DEL、NT631;4-BP INS、NT732;TYR35TER;ASP37VAL;SER58CYS;ILE102SER;ASN274SER;1-BP INS、112A;4-BP DEL、211CTCT;
ILE125LYS;ALA175THR;ILE316SER;TYR287TER;ASN97ASP;15-BP DEL(δ88-92密码子);和SER127LEU。将OMIM数据库的相关部分引入本文作为参考。
在实施例实施方案中,MC4R突变导致MC4R信号传导活性保留。
可以通过本领域技术人员众所周知的方法检测编码MC4R的基因组序列中的突变。例如,可以使用核苷酸引物例如Farooqi等人,The Journal of Clinical Investigation,2000年7月,106卷(2),pp.271-279和Vaisse等人,The Journal of ClinicalInvestigation,2000年7月,106卷(2),pp.253-262中所述的引物克隆所述基因组序列,并且使用商购测序仪和软件分析克隆的序列。
可以通过本领域技术人员众所周知的方法测定MC4R的活性。例如,可以用克隆的MC4R DNA瞬时转染细胞,使转染的细胞接触MC4R激动剂(例如α-MSH),并且通过例如Roubert等人在Journal of Endocrinology(2010)207,pp.177-183中所述的电化发光测定法测定cAMP即MC4R的第二信使的胞内水平。可以通过比较作为对野生型MC4R的指定激动剂响应产生的cAMP胞内水平与突变MC4R产生的cAMP胞内水平确定MC4R信号传导减少。
MC4R调节剂(例如激动剂)还可以用于治疗患有其它障碍的患者,例如MC4R天然激动剂的利用度降低。这类患者的实例包括对于在瘦素依赖性途径中重要的基因中的突变(Nature Clinical Practice Endocrinology and Metabolism,2006;2;6;318和N Eng JMed:2007;356;3;237)、阿黑皮素加工(Nature Genetics,1998,155;Cell Metabolism,2006;3;135;Annals Acad Med,2009,38;1;34)或编码前蛋白转化酶类的基因中的突变为杂合或纯合的个体。
施用方式
用于实施本文所述方法的化合物或其药学上可接受的盐或包含本发明化合物或药学上可接受的盐的组合物的施用可以是连续的,每小时1次,每日4次,每日3次,每日2次,每日1次,隔天1次,每周2次,每周1次,每隔2周1次,每月1次或每隔2个月或更长时间1次或一些另外的间歇式给药方案。
本发明化合物或包含本发明化合物或其可药用盐的组合物施用的实例包括外周施用。外周施用的实例包括口服、皮下、腹膜内、肌内、静脉内、直肠、透皮、口含、舌下、吸入、肺或鼻内施用形式。
联合疗法
本文所述的肽可以用于治疗响应于MC4R调节的障碍的任意种,通过施用与一种或多种另外的药物活性化合物(“第二种活性剂”)的组合来进行。这种组合施用可以通过包括一种或多种本文所述的肽类和一种或多种第二种活性剂的单一剂型来进行,这种单一剂型包括片剂、胶囊、喷雾剂、吸入粉末、可注射液体等。或者,组合施用可以通过施用两种不同剂型来进行,其中一种剂型包含一种或多种本文所述的肽类,而另一种剂型包括一种或多种第二种活性剂。在这种情况中,所述剂型可以相同或不同。不意味着限制联合疗法,下文示例了可以使用的一些联合疗法。
可以将本文所述的肽与一种或多种用于治疗不同与体重和进食相关的障碍例如肥胖和/或超重的第二种活性剂组合。特别地,第二种活性剂可以是减肥药,其影响能量消耗、醣酵解、糖原异生、糖原分解、脂解、脂肪生成、脂肪吸收、脂肪储存、脂肪排泄、饥饿和/或饱满感和/或渴望机制、食欲/动机、食物摄入或胃肠活动。减少能量摄取的药物部分包括不同的药理学活性剂,称作食欲减退剂,它们作为辅剂用于减体重程序中的行为疗法。
通常,肥胖控制剂或药物的总剂量在与一种或多种本文所述的肽组合时可以为0.1-3,000mg/天,优选约1-1,000mg/天,且更优选约1-200mg/天,分单次剂量或2-4次分次剂量。然而,确切剂量由主治医师决定且依赖于例如施用的化合物效能、患者年龄、体重、病情和响应这样的因素。
可以将本文所述的一种或多种肽类与用于治疗糖尿病的一种或多种第二种活性剂组合。
此外,或者,还可以将本文所述的一种或多种肽类与用于治疗与肥胖和/或超重相关的疾病、障碍和/或病症的一种或多种第二种活性剂组合,所述与肥胖和/或超重相关的疾病、障碍和/或病症例如胰岛素抵抗;葡萄糖耐量降低;2型糖尿病;代谢综合征;血脂异常(包括高脂血症);高血压;心脏病(例如冠心病,心肌梗死);心血管障碍;非酒精性脂肪肝病(包括非酒精性脂肪性肝炎;关节障碍(包括继发性骨关节炎);胃食管反流;睡眠呼吸暂停;动脉粥样硬化;中风;大血管病和微血管病;皮脂腺病(例如肝中);胆石;和胆囊障碍。
第二种活性剂
所述一种或多种第二种活性剂选自,例如:
胰岛素和胰岛素类似物;
胰岛素促泌素,包括磺脲类(例如格列吡嗪)和膳食葡萄糖调节剂(有时称作“短效促泌素”),例如氯茴苯酸类(例如瑞格列奈和那格列奈);
改善肠降血糖素作用的活性剂:肠降血糖素,肠降血糖素模拟物,改善肠降血糖素功能的活性剂,例如GLP-1、GIP;GLP-1激动剂(例如艾塞那肽和利拉糖肽(VICTOZA))、DPP-4抑制剂(例如维格列汀、沙格列汀和西格列汀);
胰岛素致敏剂,包括过氧化物酶体增殖物激活受体γ(PPARγ)激动剂,例如噻唑烷二酮类(例如吡格列酮和罗格列酮),和具有PPARα、γ和δ活性的任意组合的活性剂;
调节肝糖平衡的活性剂,例如双胍类(例如二甲双胍)、果糖1,6-二磷酸酶抑制剂、糖原磷酸化酶抑制剂、糖原合成酶激酶抑制剂和葡糖激酶激活物;
为减少/减缓葡萄糖从肠中吸收设计的活性剂,例如α葡糖苷酶抑制剂(例如米格列醇和阿卡波糖);
拮抗糖原作用或减少其分泌的活性剂,例如白糊精类似物(例如普兰林肽);
防止葡萄糖被肾重吸收的活性剂,例如钠离子依赖的葡糖转运蛋白2(SGLT-2)抑制剂(例如达格列净);
为治疗延长的高血糖症并发症设计的活性剂,例如醛糖还原酶抑制剂(例如依帕司他和雷尼司他);
用于治疗与微血管病相关的并发症的活性剂;
抗血脂异常药,例如HMG-CoA还原酶抑制剂(他汀类药物,例如瑞舒伐他汀)和其它降胆甾醇药;
PPARα激动剂(贝特类,例如吉非罗齐和非诺贝特);
胆汁酸多价螯合剂(例如考来烯胺);
胆固醇吸收抑制剂(例如植物甾醇类(即植物甾醇),合成抑制剂);
胆固醇酯转移蛋白(CETP)抑制剂;回肠胆汁酸转运系统抑制剂(IBAT抑制剂);
胆汁酸结合树脂类;
烟酸(尼克酸)及其类似物;
抗氧化剂,例如普罗布考;
ω-3脂肪酸;
抗高血压药,包括肾上腺素能受体拮抗剂,例如β-阻滞剂(例如阿替洛尔),α阻滞剂(例如多沙唑嗪)和混合型α/β阻滞剂(例如拉贝洛尔);
肾上腺素能受体激动剂,包括α-2激动剂(例如可乐定);
血管紧张素转换酶(ACE)抑制剂(例如赖诺普利),钙通道阻滞药,例如二氢吡啶类(例如硝苯地平),苯基烷基胺类(例如维拉帕米)和苯并噻氮卓类(例如地尔硫卓);
血管紧张素II受体拮抗剂(例如坎地沙坦);醛固酮受体拮抗剂(例如依普利酮);
中枢作用肾上腺素能药,例如中枢α激动剂(例如可乐定);和利尿剂(例如呋塞米);
止血调节剂,包括抗血栓药,例如纤维蛋白溶解激活物;
凝血酶拮抗剂;
因子VIIa抑制剂;抗凝血药,例如维生素K拮抗剂(例如华法林)、肝素及其低分子量类似物、因子Xa抑制剂和直接凝血酶抑制剂(例如阿加曲班);抗血小板剂,例如环加氧酶抑制剂(例如阿司匹林)、腺苷二磷酸(ADP)受体抑制剂(例如氯吡格雷)、磷酸二酯酶抑制剂(例如西洛他唑)、糖蛋白IIB/IIA抑制剂(例如替罗非班)和腺苷再摄取抑制剂(例如双嘧达莫);
减肥药,例如食欲抑制剂(例如麻黄碱),包括去甲肾上腺素能药(例如芬特明)和血清素能类药、胰脂肪酶抑制剂(例如奥利司他)、微粒体转移蛋白(MTP)调节剂、二酰基甘油酰基转移酶(DGAT)抑制剂和大麻素(CB1)受体拮抗剂(例如利莫纳班);
摄食行为调节剂,例如阿立新受体调节剂和黑素浓集激素(MCH)调节剂;
神经肽Y(NPY)/NPY受体调节剂;
丙酮酸脱氢酶激酶(PDK)调节剂;
5-羟色胺受体受体调节剂;
瘦素/瘦蛋白受体调节剂;
葛瑞林/葛瑞林受体调节剂;
增强β细胞功能的活性剂;
刺激能量消耗的活性剂(例如β肾上腺素能刺激剂、UCP-1激动剂、棕色脂肪调节剂和刺激剂);
诱导脂细胞裂解的活性剂(例如抗体);
烟碱或烟碱戒断助剂;
雌激素,雌激素受体的天然或合成调节剂;
μ-阿片样物质受体调节剂;和
单胺转移调节剂,例如选择性5-羟色胺再摄取抑制剂(SSRI)(例如氟西汀)、去甲肾上腺素再摄取抑制剂(NARI)、去甲肾上腺素-5-羟色胺再摄取抑制剂(SNRI)、三元单胺再摄取阻滞剂(例如替索芬辛)和单胺氧化酶抑制剂(MAOI)(例如托洛沙酮和阿米夫胺)或其药学上可接受的盐。
在一个实施例实施方案中,将MC4R激动剂和第二种活性剂与施用极低热量饮食(VLCD)或低热量饮食(LCD)同时、依次或单独施用。
本发明分离的多肽类
在一个实施例实施方案中,分离的多肽类(例如MC4R激动剂)是式(I)的那些或其药学上可接受的盐:
具有如下结构式(I)的分离的多肽:
或其药学上可接受的盐,
其中:
R1是H或C1-C6酰基;
R2是-NR3R4或-OR5,其中R3、R4和R5各自独立地是H或C1-C6烷基;
A1是选自Arg、Lys、Orn、His、Nle、Phe、Val、Leu、Trp、Tyr、Ala、Ser、Thr、Gln、Asn、Asp、Glu或TzAla的氨基酸残基;或
A1是选自如下的部分:任选取代的C1-C12烷基、任选取代的C6-C18芳基、任选取代的C5-C18杂芳基、芳烷基,其中所述芳基部分是任选取代的C6-C18芳基,且所述烷基部分是任选取代的C1-C12烷基或杂芳烷基,其中所述杂芳基部分是任选取代的C5-C18杂芳基,且所述烷基部分是任选取代的C1-C12烷基;
A2和A8各自独立地是选自Cys、hCys、Pen、Asp、Glu、Lys、Orn、Dbu或Dpr的氨基酸残基,其中A2和A8配对选择以便能够在其相应的侧链之间形成共价键;
A3不存在或是选自Ala、Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn、Aib或残基Y的氨基酸残基,其中Y是选自由如下结构式表示的氨基酸的氨基酸:
其中:
R11和R12各自独立地是H、-CH3、苯基或苄基;
R21、R22、R23和R24各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
R31、R32、R33、R34、R41、R42和R43各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
A4不存在或是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、任选取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基,其中X是选自由如下结构式表示的氨基酸的氨基酸:
其中:
R51和R52各自独立地是H、-CH3、苯基或苄基;
R61、R62、R63和R64各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
R71、R72、R73、R74、R81、R82和R83各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
A5是任选取代的Phe、任选取代的1-Nal或任选取代的2-Nal;
A6是Arg;且
A7是Trp,其中任意的氨基酸残基是L-或D-构型。
在实施例实施方案中,A3不存在或是选自Ala、Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn或Aib的氨基酸残基;且A4不存在或是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、任选取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基,其中X是由如下结构式表示的氨基酸:
其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中,A3和A4各自独立地是选自由如下结构式表示的氨基酸的氨基酸残基:
其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中,A3和A4不是都不存在。其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中,当A4是氨基酸时,A3不是Aib或Gly。其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中,当A4是His且A5是D-Phe或2-Nal时,A3不是D-氨基酸或L-Ala。其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中,当A2和A8各自选自Cys、hCys或Pen时:(a)当A4不存在时,则A3不是L-His;(b)当A3不存在时,则A4不是L-His;和(c)当A4是His时,则A3不是Glu、Leu或Lys。其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中:1)A3和A4不是都不存在;2)当A4是氨基酸时,A3不是Aib或Gly;和3)当A4是His且A5是D-Phe或2-Nal时,A3不是D-氨基酸或L-Ala;4)当A2和A8各自选自Cys、hCys或Pen时:(a)当A4不存在时,则A3不是L-His;(b)当A3不存在时,则A4不是L-His;和(c)当A4是His时,则A3不是Glu、Leu或Lys。其余变量的值和优选值如上下文中对式(I)所定义。
在另一个实施方案中,式(I)的多肽类,A4是L-氨基酸。在其它实施方案中,A4不存在。其余变量的值和优选值如上下文中对式(I)所定义。
在实施例实施方案中,A5可以是任选取代的1-Nal或任选取代的2-Nal,例如任选取代的D-2-Nal。A5可以在任意5个芳族碳上被选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2或-OCH3的取代基取代。
在另一个实施方案中,式(I)的多肽类,A5是任选取代的D-Phe。A5可以在任意5个芳族碳上被选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2或-OCH3的取代基取代。A5的适合的实例包括、但不限于选自如下的D-氨基酸残基:Phe、Phe(2’-F)、Phe(2’-Cl)、Phe(2’-Br)、Phe(2’-I)、Phe(2’-CN)、Phe(2’-CH3)、Phe(2’-OCH3)、Phe(2’-CF3)、Phe(2’-NO2)、Phe(3’-F)、Phe(3’-Cl)、Phe(3’-Br)、Phe(3’-I)、Phe(3’-CN)、Phe(3’-CH3)、Phe(3’-OCH3)、Phe(3’-CF3)、Phe(3’-NO2)、Phe(4’-F)、Phe(4’-Cl)、Phe(4’-Br)、Phe(4’-I)、Phe(4’-CN)、Phe(4’-CH3)、Phe(4’-OCH3)、Phe(4’-CF3)、Phe(4’-NO2)、Phe(4’-t-Bu)、Phe(2’,4’-二F)、Phe(2’,4’-二Cl)、Phe(2’,4’-二Br)、Phe(2’,4’-二I)、Phe(2’,4’-二-CN)、Phe(2’,4’-二-CH3)、Phe(2’,4’-二-OCH3)、Phe(3’,4’-二F)、Phe(3’,4’-二Cl)、Phe(3’,4’-二Br)、Phe(3’,4’-二I)、Phe(3’,4’-二-CN)、Phe(3’,4’-二-CH3)、Phe(3’,4’-二-OCH3)、Phe(3’,5’-二F)、Phe(3’,5’-二Cl)、Phe(3’,5’-二Br)、Phe(3’,5’-二I)、Phe(3’,5’-二-CN)、Phe(3’,5’-二CH3)、Phe(3’,5’-二-OCH3)或Phe(3’,4’,5’-三F)。其余变量的值和优选值如上下文中对式(I)所定义。
在另一个实施方案中,式(I)的多肽类,A5是任选取代的D-2-Nal。A5可以在任意5个芳族碳上被选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2或-OCH3的取代基取代。
在另一个实施方案中,式(I)的多肽类,A4是在任意可取代的位置上被选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2、苄基或-OCH3的取代基取代的His。其余变量的值和优选值如上下文中对式(I)所定义。
在一个具体的实施方案中,本发明的化合物是式(I)的那些多肽类,其具有对于MC4R的EC50约为0.01nM-约10nM,例如0.01-3nM,同时具有的EC50(MC1R)/EC50(MC4R)之比至少为10。
在另一个实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括如下结构式的任意一种:
或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括如下结构式的任意一种表示的多肽:
或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由式(I)表示的多肽,其中A4是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基。这种肽类的实例包括由如下结构式任意一种表示的肽类:
Ac-Arg-环[Cys-D-Ala-His(3-Me)-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:36)
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:37)
Ac-Arg-环[Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:9)Ac-Arg-环[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:8)Ac-Arg-环[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:7)Ac-Arg-环[Cys-D-Ala-Arg-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:38)Ac-Arg-环[Cys-D-Ala-Tyr-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:39)Ac-Arg-环[Cys-D-Ala-D-Pro-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:40)Ac-Arg-环[Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:2)Ac-Arg-环[Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys]-NH2;(SEQ ID NO:4)
Ac-Arg-环[Cys-D-Ala-Atc-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:41)Ac-Arg-环[Cys-D-Ala-QAla-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:42)Ac-Arg-环[Cys-D-Ala-sChp-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:43)或
Ac-Arg-环[Cys-D-Ala-X-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:44)或其药学上可接受的盐。
在实施例实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
Ac-Arg-环[hCys-Ala-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:15)Ac-Arg-环[hCys-D-Ala-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:14)Ac-Arg-环[hCys-D-Ala-D-Phe-Arg-Trp-Pen]-NH2;(SEQ ID NO:45)Ac-Arg-环[Glu-D-Ala-D-Phe-Arg-Trp-Dpr]-NH2;(SEQID NO:26)Ac-Arg-环[Glu-Ala-D-Phe-Arg-Trp-Dpr]-NH2;(SEQ ID NO:27)
Ac-Arg-环[hCys-Aib-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:46)Ac-Arg-环[hCys-Sar-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:47)Ac-Arg-环[hCys-Val-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:48)Ac-Arg-环[hCys-D-Val-D-Phe-Arg-Trp-Cys]-NH2;(SEQ IDNO:49)Ac-Arg-环[hCys-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:50)Ac-Arg-环[hCys-D-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:51)Ac-Arg-环[hCys-Ala-D-Phe-Arg-Trp-Pen]-NH2;(SEQ ID NO:52)Ac-Arg-环[D-Pen-D-Ala-D-Phe-Arg-Trp-hCys]-NH2;(SEQ IDNO:53)Ac-Arg-环[Cys-D-Ala-D-Phe-Arg-Trp-hCys]-NH2;(SEQ ID NO:17)Ac-Arg-环[Pen-D-Ala-D-Phe-Arg-Trp-hCys]-NH2;(SEQ ID NO:54)Ac-Arg-环[D-hCys-D-Ala-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:55)Ac-Arg-环[hCys-Pro-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:20)或Ac-Arg-环[hCys-D-Pro-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:56)或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由式(I)表示的多肽类,其中A3是选自Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn或Aib的氨基酸残基;且A4是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基。这种多肽类的实例是由如下结构式的任意一种表示的多肽类:
Ac-Arg-环[Cys-Val-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:57)Ac-Arg-环[Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:11)或
Ac-Arg-环[Cys-D-Val-His(1-Me)-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:58)
或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
Ac-TzAla-环[Cys-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:59)或
Ac-Glu-环[Cys-Ala-His-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:60)或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:37)
Ac-Arg-环[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:8)或Ac-Arg-环[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:7)或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
Ac-Arg-环[Cys-D-Leu-His-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:61)
Ac-Arg-环[Cys-D-Ile-His-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:62)
Ac-Arg-环[Cys-D-Tle-His-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:63)或
Ac-Arg-环[Cys-D-Val-His-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:10)或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-2-Nal-Arg-Trp-Cys]-NH2;(SEQ ID NO:64)
Ac-Arg-环[Cys-D-Ala-Gln-D-2-Nal-Arg-Trp-Cys]-NH2;(SEQ ID NO:65)或
Ac-Arg-环[Cys-D-Ala-Asn-D-2-Nal-Arg-Trp-Cys]-NH2,(SEQ ID NO:66)或其药学上可接受的盐。
在另一个实施方案中,本发明的多肽类包括由如下结构式的任意一种表示的多肽:
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys]-OH;(SEQ ID NO:67)
Ac-Arg-环[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-OH;(SEQ ID NO:68)或
Ac-Arg-环[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-OH,(SEQ ID NO:69)或其药学上可接受的盐。
示例
肽合成
可以通过常规的固相肽合成制备本发明的肽类。以逐步的方式使肽链从其C-末端氨基酸衍生物开始延伸,所述C-末端氨基酸衍生物偶联在适当选择的已知适合于肽合成的固相支持物树脂上。为了合成具有C-末端酰胺官能团的肽,将Rink酰胺MBHA树脂用作固相支持物。为了合成具有C-末端游离羧基官能团的肽类,使用例如2-氯三苯甲基氯树脂、Wang或Merrifield树脂这样的树脂,它们与Fmoc-氨基酸形成酯键。大部分这些酯连接的Fmoc-氨基酸-树脂类型购自不同来源且一般在切实可行时使用。
二硫化物-环化肽类的合成
使用固相肽合成仪上的Fmoc化学组装二硫化物环肽类的线性衍生物。将Fmoc-Rink酰胺树脂放入反应容器,用NMP溶胀。然后用20%哌啶的NMP溶液处理15分钟,然后用NMP洗涤3次。对树脂进行阳性Kaiser测试(Kaiser,E.,Colescot、R.L.,Bossinge,C.D.&Cook,P.I.Anal.Biochem.,1990,34:595-598)。将其重新混悬于NMP,与所需的第一种C-末端Fmoc-氨基酸衍生物和HOBt混合。通过添加HBTU试剂和DIPEA启动偶合反应。在混合2-3小时后,通过在从该反应混合物中抽取的树脂的小等分部分上的阴性Kaiser试验证实偶合完成。然后用NMP将树脂洗涤3次。此后,如上所述除去Fmoc基团,用所述的第二种C-末端Fmoc-氨基酸衍生物重复整个循环。用新到来的氨基酸各自依次重复同一反应循环。使用氯醌显色试验(Vojkovsky,T.Pept.Res.,1995,8:236-237)替代Kaiser试验,用于Fmoc从肽序列上的脯氨酸残基上脱保护的阳性测试,也用于测试氨基酸与脯氨酸完全偶合(阴性氯醌试验)。在具有N-末端乙酰基的肽类的情况中,用乙酐和吡啶将Fmoc脱保护的肽树脂处理10分钟。用NMP、二氯甲烷洗涤Kaiser试验测试阴性后的树脂,真空干燥。Fmoc-氨基酸衍生物用于合成这些肽类。所用的三官能团氨基酸衍生物如下:Fmoc-Cys(Trt)-OH,Fmoc-Trp(Boc)-OH,Fmoc-Arg(Pbf)-OH,Fmoc-His(Trt)-OH,Fmoc-Asn(Trt)-OH,Fmoc-Gln(Trt)-OH,Fmoc-hCys(Trt)-OH,Fmoc-Pen(Trt)-OH,Fmoc-Tyr(But)-OH,Fmoc-His(1-Me)-OH,Fmoc-His(3-Me)-OH和Fmoc-Glu(OBut)-OH。
为了从树脂上裂解掉肽和使侧链官能团脱保护,将肽树脂溶于:2%TIS/5%水/5%(w/v)DTT/88% TFA。将该溶液混合3.5小时,然后过滤。将滤液与冷无水乙醚混合。通过离心采集沉淀。滗析溶剂,将肽沉淀重新混悬于新鲜乙醚。将乙醚后处理重复2次以上。真空干燥肽。将粗的线性肽产物稀释至在5%乙酸中2mg/mL浓度,在剧烈搅拌下滴加0.5M碘/甲醇,直到得到持续的淡黄色溶液。将该溶液再搅拌10分钟。然后通过添加1M硫代硫酸钠在混合中使过量的碘猝灭,直到该混合物变成无色为止。冻干环化的肽溶液,通过制备型HPLC、使用反相C-18柱纯化粗粉末。收集纯化的产物级分,冻干。通过质谱法,使用电喷雾电离技术分析肽类,鉴定为正确质量。
内酰胺(Lactm)-环化肽类的合成
还通过标准固相肽合成方法合成环内酰胺肽类。对于具有C-末端Dpr的肽类,将Fmoc-Dpr(Mtt)-BHA树脂转入固相肽合成仪反应器。如上所述除去Fmoc基团,接下来使Fmoc-保护的氨基酸、例如Fmoc-Trp(Boc)-OH与所述树脂通过标准偶合方法偶合。除去Fmoc保护基,按照正确的顺序,通过重复偶合和脱保护操作各自添加其余的氨基酸,直到氨基酸序列完成。对于谷氨酸,使用偶合Fmoc-Glu(OPip)。然后同样地如上述二硫化物系列肽类所述,在N-末端上使组装完全的肽乙酰化。然后除去正交保护的侧链。例如,通过用1% TFA的二氯甲烷溶液处理裂解具有正交保护的Glu侧链为2-苯基异丙基酯(OPip)或Dpr保护为4-甲基三苯甲基(Mtt)的肽。将脱保护的肽树脂混悬于NMP。用HBTU/DIPEA处理。环化后(阴性Kaiser试验),用DCM洗涤肽-树脂,干燥。使用三氟乙酸(TFA)在水和1,2-乙二硫醇(EDT)的存在下从树脂上裂解环肽与任何其余的保护基。在添加冷无水乙醚时通过沉淀采集产物,通过离心采集。最终纯化通过反相HPLC、使用反相C-18柱进行。通过冻干采集纯化的肽,通过质谱、使用电喷雾方法分析其质量。
本发明化合物的实施例如表2中所示。
表2:本发明的实施例化合物
放射性配体结合测定:
用于测定从本发明环肽的受体上置换放射性标记的配体的结合常数(Kd)或抑制浓度(IC50)的受体结合测定可以通过本领域公知的任意方式进行。
作为实例,由为稳定表达hMC受体亚型1、3、4或5而转染的CHO-K1细胞制备用于结合测定的细胞膜制品。[125I](Tyr2)-(Nle4-D-Phe7)-α-MSH([125I]-NDP-α-MSH结合的竞争性抑制在聚丙烯96孔板中进行。简言之,在37℃将如上所述制备的细胞膜(1-10μg蛋白/孔)在pH 7.4的包含0.2%BSA、5mM MgCl2、1mM CaCl2和0.1mg/mL杆菌肽的50mM Tris-HCl中与递增浓度的测试化合物和0.1-0.3nM[125I]-NDP-α-MSH一起温育约120分钟。通过经预先浸渍0.1%(w/v)聚乙稀亚胺(PEI)的GF/C玻璃纤维滤板(Meriden,CT,USA)过滤从游离[125I]-NDP-α-MSH中分离结合的[125I]-NDP-α-MSH配体。在约0-4℃温度下用pH 7.4的50mM Tris-HCl将滤器洗涤3次,然后测定放射性。通过计算机辅助的非线性回归分析分析结合数据。
环AMP刺激测定
用于测定本发明的环肽的激动剂或激动剂状态的功能性测定可以通过本领域公知的任意方式进行。
电化发光(ECL)测定
以剂量依赖性方式,通过电化发光(ECL)测定法测定所述肽类对胞内环AMP(cAMP)水平的刺激(Meso Scale Discovery,Gaithersburg,MD,USA;下文称作"MSD")。简言之,将稳定表达hMC受体亚型的CHO-K1细胞混悬于RMPI测定缓冲液(RMPI 1640缓冲液包含0.5mM IBMX和0.2%蛋白质混合物(MSD阻滞剂A))。将稳定表达hMC受体亚型1、3、4或5的约7,000细胞/孔的转基因CHO-K1细胞调配在包含集成碳电极的384-孔多阵列板(MSD)中,用抗-cAMP抗体包被。加入递增浓度的测试化合物,将细胞在37℃温育约40分钟。加入包含0.2%蛋白质混合物和2.5nM TAGTM钌标记的cAMP(MSD)的细胞裂解缓冲液(具有MgCl2和Triton的HEPES-缓冲的盐水溶液,pH 7.3),将细胞在室温温育约90分钟。在第二个温育期结束时,加入读取缓冲液(包含ECL共反应剂和Triton X-100的Tris-缓冲溶液,pH7.8),通过使用Sector Imager 6000(MSD)ECL检测即刻测定细胞裂解液中的cAMP水平。使用计算机辅助的非线性回归分析(XL拟合;IDBS)分析数据,报道为EC50值。EC50表示得到最大反应响应的50%、例如如使用上述测定法测定的cAMP最高水平的50%所需的激动剂化合物浓度。
cAMP测量试验
使人MC4-R转染的细胞生长至在96孔板中汇合(以约250,000细胞/孔铺板)。用0.2mM异丁基甲基黄嘌呤(IBMX)和分等级浓度的肽或在20nM NDP-MSH存在下的肽处理细胞,一式三份的组。类似地,仅用20nM NDP-MSH处理的细胞用作阳性对照,体积为200μL。还包括用作阴性对照的缓冲液空白。在37℃温育1小时后,通过添加50μL细胞裂解缓冲液裂解细胞。使用商购低pH cAMP测定试剂盒(Amersham BioSciences),按照试剂盒供应商指定的方法对250μL这种温育培养基中蓄积的总cAMP进行定量。将显示在相同或高于作为阳性对照的α-MSH的范围内的cAMP蓄积的肽视为激动剂。将激动剂数据绘图,使曲线拟合,以测定EC50值。显示在与阴性对照(在没有α-MSH的存在下的缓冲液空白)相同范围内蓄积的肽在测试浓度下无效。如果当测定中也存在α-MSH时存在cAMP抑制,则将显示减弱的蓄积的肽视为拮抗剂。类似的测定可以使用hMC-1R、hMC-3R和hMC-5R细胞进行。
使用β-半乳糖苷酶(β-Gal)报道系统的cAMP蓄积测量
应用使用具有β-半乳糖苷酶(β-Gal)作为功能报道系统的酶片段互补(EFC)系统的化学发光读出系统。用于不同黑皮质素受体系统的这种测定系统是商购的(cAMP HunterGPCR测定系统,Discoverx Corp,Fremont,CA)。该测定法使用分裂成两个互补部分的β-Gal酶;用于酶受体的EA和用于酶供体的ED。在该测定法中,形成与cAMP融合的ED部分以便与由细胞生成的cAMP竞争性结合cAMP-特异性抗体。然后添加EA以便与任何未结合的ED-cAMP形成活性β-Gal。然后这种活性酶将化学发光底物转化成输出信号,其被记录在标准微量培养板读出器上。
简言之,将每个孔10000个细胞铺板过夜,然后在37℃将每个孔(与10μl测定缓冲液一起温育的细胞)与在细胞测定缓冲液(5μL)中的4X顺序浓度的测试化合物和cAMP抗体试剂(5μL)一起温育30min。然后加入包含ED-cAMP偶合的酶片段和报道底物(Emerald II-Galacton Star,5:1)的细胞裂解缓冲液(20μL),在室温温育60min。接下来加入20μL EAβ-Gal片段试剂。在室温再温育120min后,通过平板读出器(Envision)测定化学发光,数据用于计算测试肽的EC50值。
结果如表3中所示。
表3:本发明实施例化合物的EC50(nM)值
尽管具体显示并且参照其实施例实施方案描述了本发明,但是本领域技术人员可以理解,可以在不脱离由待批权利要求涵盖的本发明范围的情况下对其中进行各种形式和内容上的各种改变。
Claims (25)
1.具有如下结构式(I)的分离的多肽:
或其药学上可接受的盐,
其中:
R1是-H或C1-C6酰基;
R2是-NR3R4或-OR5,其中R3、R4和R5各自独立地是H或C1-C6烷基;
A1是选自Arg、Lys、Orn、His、Nle、Phe、Val、Leu、Trp、Tyr、Ala、Ser、Thr、Gln、Asn、Asp、Glu或TzAla的氨基酸残基;或
A1是选自如下的部分:任选取代的C1-C12烷基、任选取代的C6-C18芳基、任选取代的C5-C18杂芳基,芳烷基,其中所述芳基部分是任选取代的C6-C18芳基,且所述烷基部分是任选取代的C1-C12烷基,或杂芳烷基,其中所述杂芳基部分是任选取代的C5-C18杂芳基,且所述烷基部分是任选取代的C1-C12烷基;或
A1不存在;或
A2和A8各自独立地是选自Cys、hCys、Pen、Asp、Glu、Lys、Orn、Dbu或Dpr的氨基酸残基,其中A2和A8配对选择以便能够在其相应的侧链之间形成共价键;
A3是选自Ala、Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn、Aib的氨基酸残基,或
A3不存在,或
A3是残基Y,其中Y是选自表示为如下结构式的氨基酸的氨基酸:
其中:
R11和R12各自独立地是H、-CH3、苯基或苄基;
R21、R22、R23和R24各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
R31、R32、R33、R34、R41、R42和R43各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
A4不存在或是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、任选取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基,其中X是选自表示为如下结构式的氨基酸的氨基酸:
其中:
R51和R52各自独立地是H、-CH3、苯基或苄基;
R61、R62、R63和R64各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
R71、R72、R73、R74、R81、R82和R83各自独立地是H、-CH3、-CF3、苯基、苄基、F、Cl、Br、I、-OCH3或-OH;
A5是任选取代的Phe、任选取代的1-Nal或任选取代的2-Nal;
A6是Arg;且
A7是Trp,
其中任意的氨基酸残基是L-或D-构型,
条件是:
1)A3和A4不是都不存在;
2)当A4是氨基酸时,A3不是Aib或Gly;和
3)当A4是His且A5是D-Phe或2-Nal时,A3不是D-氨基酸或L-Ala
4)当A2和A8各自选自Cys、hCys或Pen时:
(a)当A4不存在时,则A3不是L-His;
(b)当A3不存在时,则A4不是L-His;和
(c)当A4是His时,则A3不是Glu、Leu或Lys。
2.权利要求1的分离的多肽,
其中:
R1是-H或C1-C6酰基;
R2是-NR3R4或-OR5,中R3、R4和R5各自独立地是H或C1-C6烷基;
A1不存在;或
A1是选自Arg、Lys、Orn、His、Nle、Phe、Val、Leu、Trp、Tyr、Ala、Ser、Thr、Gln、Asn、Asp、Glu或TzAla的氨基酸残基;或
A1是选自如下的部分:选取代的C1-C12烷基、任选取代的C6-C18芳基、任选取代的C5-C18杂芳基、芳烷基,其中所述芳基部分是任选取代的C6-C18芳基,且所述烷基部分是任选取代的C1-C12烷基,或杂芳烷基,其中所述杂芳基部分是任选取代的C5-C18杂芳基,且所述烷基部分是任选取代的C1-C12烷基;
A2和A8各自独立地是选自Cys、hCys、Pen、Asp、Glu、Lys、Orn、Dbu或Dpr的氨基酸残基,其中A2和A8配对选择以便能够在其相应的侧链之间形成共价键;
A3不存在或选自Ala、Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn或Aib的氨基酸残基;
A4不存在或选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、任选取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基,其中X是表示为如下结构式的氨基酸:
A5是任选取代的Phe、任选取代的1-Nal或任选取代的2-Nal;
A6是Arg;且
A7是Trp,
其中任意的氨基酸残基是L-或D-构型。
3.权利要求1或2的多肽,其中A3是D-氨基酸。
4.权利要求1或2的多肽,其中A4是L-氨基酸。
5.权利要求1或2的多肽,其中A4不存在。
6.权利要求1-5的多肽,其中A5是任选取代的D-Phe。
7.权利要求1-6的多肽,其中A5在任意5个芳族碳上任选地被选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2或-OCH3的取代基取代。
8.权利要求1-6的多肽,其中A5是选自如下的D-氨基酸残基:
Phe、Phe(2’-F)、Phe(2’-Cl)、Phe(2’-Br)、Phe(2’-I)、Phe(2’-CN)、Phe(2’-CH3)、Phe(2’-OCH3)、Phe(2’-CF3)、Phe(2’-NO2)、Phe(3’-F)、Phe(3’-Cl)、Phe(3’-Br)、Phe(3’-I)、Phe(3’-CN)、Phe(3’-CH3)、Phe(3’-OCH3)、Phe(3’-CF3)、Phe(3’-NO2)、Phe(4’-F)、Phe(4’-Cl)、Phe(4’-Br)、Phe(4’-I)、Phe(4’-CN)、Phe(4’-CH3)、Phe(4’-OCH3)、Phe(4’-CF3)、Phe(4’-NO2)、Phe(4’-t-Bu)、Phe(2’,4’-二F)、Phe(2’,4’-二Cl)、Phe(2’,4’-二Br)、Phe(2’,4’-二I)、Phe(2’,4’-二-CN)、Phe(2’,4’-二-CH3)、Phe(2’,4’-二-OCH3)、Phe(3’,4’-二F)、Phe(3’,4’-二Cl)、Phe(3’,4’-二Br)、Phe(3’,4’-二I)、Phe(3’,4’-二-CN)、Phe(3’,4’-二-CH3)、Phe(3’,4’-二-OCH3)、Phe(3’,5’-二F)、Phe(3’,5’-二Cl)、Phe(3’,5’-二Br)、Phe(3’,5’-二I)、Phe(3’,5’-二-CN)、Phe(3’,5’-二CH3)、Phe(3’,5’-二-OCH3)或Phe(3’,4’,5’-三F)。
9.权利要求1-4或6-8的多肽,其中A4是在任意可取代的位置上被选自F、Cl、Br、I、-CH3、-OH、-CN、胺、-NO2或-OCH3的取代基取代的His。
10.权利要求1或2的多肽,表示为如下结构式的任意一种:
或其药学上可接受的盐。
11.权利要求1或2的多肽,表示为如下结构式的任意一种:
或其药学上可接受的盐。
12.权利要求1或2的多肽,表示为如下结构式的任意一种:
或其药学上可接受的盐。
13.权利要求1或2的多肽,其中A4是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基。
14.权利要求13的多肽,表示为如下结构式的任意一种:
Ac-Arg-环[Cys-D-Ala-His(3-Me)-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:36)
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:37)
Ac-Arg-环[Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:9)Ac-Arg-环[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:8)Ac-Arg-环[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:7)Ac-Arg-环[Cys-D-Ala-Arg-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:38)Ac-Arg-环[Cys-D-Ala-Tyr-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:39)Ac-Arg-环[Cys-D-Ala-D-Pro-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:40)Ac-Arg-环[Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:2)Ac-Arg-环[Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys]-NH2;(SEQ ID NO:4)
Ac-Arg-环[Cys-D-Ala-Atc-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:41)Ac-Arg-环[Cys-D-Ala-QAla-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:42)Ac-Arg-环[Cys-D-Ala-sChp-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:43)或
Ac-Arg-环[Cys-D-Ala-X-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:44)或其药学上可接受的盐。
15.权利要求1或2的多肽,表示为如下结构式的任意一种:
Ac-Arg-环[hCys-Ala-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:15)
Ac-Arg-环[hCys-D-Ala-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:14)
Ac-Arg-环[hCys-D-Ala-D-Phe-Arg-Trp-Pen]-NH2;(SEQ ID NO:45)
Ac-Arg-环[Glu-D-Ala-D-Phe-Arg-Trp-Dpr]-NH2;(SEQ ID NO:26)
Ac-Arg-环[Glu-Ala-D-Phe-Arg-Trp-Dpr]-NH2;(SEQ ID NO:27)
Ac-Arg-环[hCys-Aib-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:46)
Ac-Arg-环[hCys-Sar-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:47)
Ac-Arg-环[hCys-Val-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:48)
Ac-Arg-环[hCys-D-Val-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:49)
Ac-Arg-环[hCys-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:50)
Ac-Arg-环[hCys-D-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:51)
Ac-Arg-环[hCys-Ala-D-Phe-Arg-Trp-Pen]-NH2;(SEQ ID NO:52)
Ac-Arg-环[D-Pen-D-Ala-D-Phe-Arg-Trp-hCys]-NH2;(SEQ ID NO:53)Ac-Arg-环[Cys-D-Ala-D-Phe-Arg-Trp-hCys]-NH2;(SEQ ID NO:17)
Ac-Arg-环[Pen-D-Ala-D-Phe-Arg-Trp-hCys]-NH2;(SEQ ID NO:54)
Ac-Arg-环[D-hCys-D-Ala-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:55)Ac-Arg-环[hCys-Pro-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:20)或Ac-Arg-环[hCys-D-Pro-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:56)或其药学上可接受的盐。
16.权利要求1或2的多肽,其中:
A3是选自Tle、Val、Leu、Ile、Cha、Pro、Ser、Thr、Lys、Arg、His、Phe、Gln、Sar、Gly、Asn或Aib的氨基酸残基;且A4是选自Atc、Ala、QAla、Aib、Sar、Ser、Thr、Pro、Hyp、Asn、Gln、取代的His、Trp、Tyr、Lys、Arg、sChp或残基X的氨基酸残基。
17.权利要求16的多肽,表示为如下结构式的任意一种:
Ac-Arg-环[Cys-Val-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:57)Ac-Arg-环[Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:11)或
Ac-Arg-环[Cys-D-Val-His(1-Me)-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:58)
或其药学上可接受的盐。
18.权利要求1或2的多肽,表示为如下结构式的任意一种:
Ac-TzAla-环[Cys-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:59)或
Ac-Glu-环[Cys-Ala-His-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:60)
或其药学上可接受的盐。
19.权利要求1或2的多肽,表示为如下结构式的任意一种:
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:37)
Ac-Arg-环[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:8)或Ac-Arg-环[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:7)或其药学上可接受的盐。
20.权利要求1或2的多肽,表示为如下结构式的任意一种:
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-2-Nal-Arg-Trp-Cys]-NH2;(SEQ ID NO:64)
Ac-Arg-环[Cys-D-Ala-Gln-D-2-Nal-Arg-Trp-Cys]-NH2;(SEQ ID NO:65)或
Ac-Arg-环[Cys-D-Ala-Asn-D-2-Nal-Arg-Trp-Cys]-NH2,(SEQ ID NO:66)或其药学上可接受的盐。
21.权利要求1或2的多肽,表示为如下结构式的任意一种:
Ac-Arg-环[Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys]-OH;(SEQ ID NO:67)
Ac-Arg-环[Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys]-OH;(SEQ ID NO:68)或Ac-Arg-环[Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys]-OH(SEQ ID NO:69)或其药学上可接受的盐。
22.如下结构式的任意一种的分离的多肽或其药学上可接受的盐:Ac-Arg-环[Cys-D-Leu-His-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:61)Ac-Arg-环[Cys-D-Ile-His-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:62)Ac-Arg-环[Cys-D-Tle-His-D-Phe-Arg-Trp-Cys]-NH2;(SEQ ID NO:63)或Ac-Arg-环[Cys-D-Val-His-D-Phe-Arg-Trp-Cys]-NH2,(SEQ ID NO:10)或其药学上可接受的盐。
23.治疗个体的对调节MC4R有响应的障碍的方法,该方法包括对有此需要的个体施用有效量的权利要求1或2的多肽或其药学上可接受的盐。
24.权利要求23的方法,其中对调节MC4R有响应的障碍是1型糖尿病、2型糖尿病、肥胖、胰岛素抵抗、代谢综合征、男性勃起功能障碍、女性性功能障碍、非酒精性脂肪肝病或非酒精性脂肪性肝炎。
25.药物组合物,包含在药学上可接受的载体中的权利要求1或2的多肽或其药学上可接受的盐。
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CA2906694A1 (en) | 2013-03-15 | 2014-09-18 | Rhythm Metabolic, Inc. | Peptide compositions |
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JP7039814B2 (ja) * | 2016-10-04 | 2022-03-23 | ディーエスエム アイピー アセッツ ビー.ブイ. | メラノコルチン-1-受容体アゴニスト |
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AU2014227712B2 (en) | 2018-08-02 |
AU2018256493A1 (en) | 2018-11-22 |
US20160017001A1 (en) | 2016-01-21 |
TR201815173T4 (tr) | 2018-11-21 |
JP7046871B2 (ja) | 2022-04-04 |
US20190092815A1 (en) | 2019-03-28 |
WO2014144260A1 (en) | 2014-09-18 |
JP2019172693A (ja) | 2019-10-10 |
CN105492456A (zh) | 2016-04-13 |
EP2970388B1 (en) | 2018-07-25 |
EP3450449A2 (en) | 2019-03-06 |
AU2021269411A1 (en) | 2021-12-16 |
AU2024200528A1 (en) | 2024-02-15 |
CA2906694A1 (en) | 2014-09-18 |
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