CN116782877A - 作为黑皮质素-4受体的选择性激动剂的用途 - Google Patents
作为黑皮质素-4受体的选择性激动剂的用途 Download PDFInfo
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- CN116782877A CN116782877A CN202180086020.3A CN202180086020A CN116782877A CN 116782877 A CN116782877 A CN 116782877A CN 202180086020 A CN202180086020 A CN 202180086020A CN 116782877 A CN116782877 A CN 116782877A
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- melanocortin
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Abstract
本发明涉及化学式1的化合物或其可药用盐作为黑皮质素‑4受体(MC4R)的选择性激动剂的用途。
Description
技术领域
本发明涉及下式1的化合物或其可药用盐作为黑皮质素-4受体(melanocortin-4receptor,MC4R)的选择性激动剂的用途:
[式1]
其中R1是C2-C5烷基。
背景技术
黑皮质素受体(MCR)是一种G蛋白偶联受体(GPCR),G蛋白的主要作用是激活第二信使并通过信号转导调节细胞对多种生理刺激的反应。迄今为止,已经鉴定了五种黑皮质素受体亚型。MC1R主要在黑素细胞和巨噬细胞中表达,并通过调节黑素细胞中的黑色素来决定皮肤和毛发的颜色。MC2R在肾上腺和脂肪组织中表达,在肾上腺中通过促肾上腺皮质激素调节肾上腺激素分泌的介导功能是众所周知的。MC3R、MC4R和MC5R不仅在神经末梢表达,而且也在脑中表达,因此认为它们通过黑皮质素肽介导中枢神经活动,表现为对行为、学习、记忆、食欲以及神经的生成和再生的影响。迄今为止,已知MC3R参与勃起功能障碍和炎症反应,已知MC4R参与肥胖症和糖尿病,并且关于各受体作用的特异性的研究正在积极进行(MacNeil DJ等,欧洲药理学杂志(Eur J Pharmacol)2002,450,93)。结果发现,在肥胖症者的遗传学研究中深度涉及MC4R基因,通过表明去除MC4R基因的敲除小鼠因暴食而发生肥胖症,证明了该受体在食欲调节中起重要作用(Lu D,Willard D等,自然(Nature)1994,371(6500),799;Huszar D等,细胞(Cell)1997,88(1),131;Hinney A等,临床内分泌学与代谢杂志(J Clin Endocrinol Metab)1990,84(4),1483)。
在黑皮质素受体之中,已知MC4R参与能量代谢和体重控制。在其它MCR亚型的情况下,由于它们参与了多种体内各种功能如皮肤色素沉着、能量稳态和外分泌功能的调节,因此确保MC4R激动剂化合物对MC4R的选择性在预防未来可能发生的副作用方面非常重要。具体而言,MC1R主要在皮肤细胞中表达,并且已知通过黑色素活动来参与皮肤色素沉着。在现有的非选择性黑皮质素受体激动剂中出现的皮肤色素沉着的副作用可能主要是由MC1R刺激能力和皮内药物蓄积引起的。因此,在现有的化合物之中,本发明人试图通过了解能够选择性激活MC4R的结构与活性之间的关系来发现能够表现出MC4R选择性的化合物(Wikberg等,欧洲药理学杂志1999,375,295-310;Wikberg等,药物研究(Pharm Res)2000,42(5)393-420;Douglas等,欧洲药物科学杂志(Eur J Pharm)2002,450,93-109;O’Rahilly等,自然医学(Nature Med)2004,10,351-352)。
发明内容
技术问题
本发明旨在提供下式1的化合物或其可药用盐作为黑皮质素-4受体(MC4R)的选择性激动剂的用途:
[式1]
其中R1是C2-C5烷基。
技术解决方案
本发明提供了一种用于预防或治疗黑皮质素受体相关疾病的药物,所述药物对黑皮质素-4受体具有选择性激动效应,其包含治疗有效量的下式1的化合物或其可药用盐:
[式1]
其中R1是C2-C5烷基。
另外,本发明提供了一种用于预防或治疗黑皮质素受体相关疾病的药物组合物,所述药物组合物对黑皮质素-4受体具有选择性激动效应,其包含治疗有效量的所述式1的化合物或其可药用盐,以及可药用载体。
另外,本发明提供了一种通过对黑皮质素-4受体的选择性激动效应来预防或治疗黑皮质素受体相关疾病的方法,所述方法包括给有此需要的对象施用治疗有效量的所述式1的化合物或其可药用盐。
另外,本发明提供了所述式1的化合物或其可药用盐作为黑皮质素-4受体选择性激动剂的用途。
以下详细描述本发明。
根据本发明的一个方面,提供了一种用于预防或治疗黑皮质素受体相关疾病的药物,所述药物对黑素皮质素-4受体具有选择性激动效应,其包含治疗有效量的所述式1的化合物或其可药用盐。
根据本发明的另一个方面,提供了一种用于预防或治疗黑皮质素受体相关疾病的药物组合物,所述药物组合物对黑皮质素-4受体具有选择性激动效应,其包含治疗有效量的所述式1的化合物或其可药用盐,以及可药用载体。
在根据本发明的一个实施方式中,所述式1的化合物是下式2的N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺:
[式2]
在根据本发明的另一个实施方式中,所述可药用盐的实例包括由下列酸形成的加成盐:无机酸,如盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸;有机羧酸,如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸和马来酸;以及磺酸,如甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸,但不限于此。在根据本发明的另一个实施方式中,所述可药用盐可选自盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸。在根据本发明的另一个实施方式中,所述可药用盐是盐酸盐。
在根据本发明的另一个实施方式中,所述式1的化合物的盐酸盐可以根据以下反应方案1制备。然而,本领域技术人员可以基于所述式1的结构,通过各种方法来制备所述式1的化合物。
[反应方案1]
在反应方案1中,
R2是C1-C5烷基;
R3是未被取代的或被1或2个C1-C5烷基取代的C3-C8环烷基;并且
R4和R5各自独立地是氢或卤素。
在根据本发明的另一个实施方式中,所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率可以为2以上。在根据本发明的另一个实施方式中,所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率可以为3以上。在根据本发明的另一个实施方式中,所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率可以为4以上。在根据本发明的另一个实施方式中,所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率可以为5以上。
在根据本发明的另一个实施方式中,所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性可以通过测量和比较受体的激动活性来证实。例如,对黑皮质素-4受体(MC4R)和黑皮质素-1受体(MC1R)的激动活性按EC50(半数最大有效浓度,诱导50%的最大激动活性的浓度)测量,于是因为在EC50的情况下,该值越低,激动能力越好,通过计算MC1R的EC50与MC4R的EC50的比率(MC1R/MC4R),可以确定该比率越大,对MC4R的选择性就越好。
在根据本发明的另一个实施方式中,所述黑皮质素受体相关疾病可选自肥胖症、糖尿病、炎症和勃起功能障碍。在根据本发明的另一个实施方式中,所述黑皮质素受体相关疾病可以是肥胖症。
在根据本发明的另一个实施方式中,所述药物或药物组合物可减少色素沉着。根据本发明的式1的化合物或其可药用盐对黑皮质素-4受体相比其它亚型的黑皮质素受体具有优异的选择性——例如,根据本发明的式1的化合物或其可药用盐对黑皮质素-4受体相比黑皮质素-1受体具有优异的选择性,从而减少皮肤色素沉着并有效预防或治疗黑皮质素受体相关疾病。
在根据本发明的另一个实施方式中,对个体对象的“治疗有效剂量”是指足以达到上述药理效果——即如上所述的治疗效果的量。所述化合物的量可以取决于所述对象的状况和严重程度、施用方式和待治疗的对象的年龄而变化,但可以由本领域普通技术人员基于他们的知识来确定。
在根据本发明的另一个实施方式中,例如,根据施用的频率和强度,所述式1的化合物的治疗有效剂量通常在大约每天0.1至500mg的范围内。成人肌内或静脉内施用的典型每日剂量在大约每天0.1至300mg的范围内,所述日剂量可以按分开的单位剂量施用。一些患者可能需要更高的日剂量。
在本发明中,除了本发明的活性成分之外,“药物组合物”还可包含其它组分,如载体、稀释剂、赋形剂等。因此,所述药物组合物可根据需要包含可药用的载体、稀释剂、赋形剂或其组合。所述药物组合物便于将化合物施用到身体内。所述化合物的各种施用方法包括但不限于口服、注射、气雾剂、肠胃外和局部施用。
在本文中,“载体”是指便于将化合物添加到细胞或组织中的化合物。例如,二甲亚砜(DMSO)是一种促进许多有机化合物施用到细胞或组织中的常规载体。
在本文中,“稀释剂”是指一种化合物,它不仅稳定生物活性形式,而且在溶解该化合物的溶剂中稀释。在该领域中,使用缓冲液中的溶解盐作为稀释剂。常规使用的缓冲液是模拟体液中的盐形式的磷酸盐缓冲盐水。由于缓冲溶液在低浓度下就可以控制溶液的pH,因此缓冲液稀释剂几乎不改变化合物的生物活性。
在本文中,“可药用的”是指不损害化合物的生物活性和物理性质的这类性质。
根据本发明的化合物可以配制为各种药物施用剂型。在本发明的药物组合物的制备中,将活性组分——具体而言,所述式1的化合物或其可药用盐——与考虑要制备的剂型而选择的可药用载体混合。例如,本发明的药物组合物可以根据需要配制为注射剂、口服制剂等。
本发明的化合物可以使用已知的药物载体和赋形剂通过常规方法配制,并插入到单元容器或多单元容器中。所述制剂可以是在油或水溶剂中的溶液、悬浮液或乳液,并且包括常规的分散剂、悬浮剂或稳定剂。另外,所述化合物可以是例如干粉形式,其在使用前溶解在灭菌的无热原水中。本发明的化合物可以通过使用常规栓剂基质如可可脂或其它甘油酯来配制成栓剂。用于口服施用的固体形式包括胶囊、片剂、丸剂、粉剂和颗粒剂。优选胶囊和片剂。片剂和丸剂优选是包有肠溶衣的。固体形式是通过将本发明的化合物与至少一种选自惰性稀释剂如蔗糖、乳糖或淀粉、润滑剂如硬脂酸镁、崩解剂、粘合剂等中的载体混合来制造的。另外,它可以配制为透皮剂型——例如,配制为洗剂、软膏剂、凝胶剂、霜剂、贴片剂或喷雾剂。
在本文中,术语“预防”是指减少或消除感染疾病的可能性。
在本文中,术语“治疗”用于指在出现疾病症状的对象中阻止、延迟或改善疾病的进展。
有利效果
根据本发明的药物或药物组合物能够有效地预防或治疗黑皮质素受体相关疾病,如肥胖症、糖尿病、炎症或勃起功能障碍,同时通过对黑皮质素-4受体优异的选择性而确保了安全性,不存在由于对其它黑皮质素受体的作用导致的副作用的风险。
附图说明
图1是根据在小鼠模型中重复施用来测量皮肤和血浆中的药物浓度的结果。
图2是在猴子的反复毒性试验中确认皮肤和皮肤毛发上的色素沉着模式的结果。
具体实施方式
以下,通过下列实施例更详细地说明本发明。然而,必须理解,本发明的保护范围不限于所述实施例。
制备例:N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-
(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐的合成
通过步骤A、B、C和D得到所述标题化合物。
步骤A:(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-
((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯的制备
将(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯盐酸盐(28.7g,82.73mmol)、(3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-甲酸(24.5g,86.87mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(22.2g,115.83mmol)、和1-羟基苯并三唑水合物(15.7g,115.83mmol)溶解在N,N’-二甲基甲酰胺(400mL)中,并缓慢添加N,N'-二异丙基乙胺(72.0mL,413.66mmol)。在室温下搅拌16小时后,将反应溶剂减压浓缩,然后添加0.5N氢氧化钠水溶液,并用乙酸乙酯进行两次提取。将有机层用氯化钠水溶液和水洗涤两次,经无水硫酸镁干燥,过滤。将滤液减压浓缩并通过柱色谱法纯化,得到标题化合物(41.19g,87%)。
MS[M+H]=575(M+1)
步骤B:(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-
((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸的制备
将在步骤A中得到的(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯(39.4g,68.62mmol)溶解在甲醇(450mL)中,并添加6N氢氧化钠水溶液(57.2mL,343.09mmol)。在室温下搅拌16小时并用6N盐酸水溶液调节pH至约5后,将反应溶液减压浓缩。将浓缩物溶解在二氯甲烷中,然后将不溶性固体用滤纸过滤。将滤液减压浓缩,得到粗产物(38.4g,99%),其无需纯化就用于下一步骤。
MS[M+H]=561(M+1)
步骤C:N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-
(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺的制备
将在步骤B中得到的(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸(38.4g,68.60mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(18.4g,96.04mmol)、和1-羟基苯并三唑水合物(13.0g,96.04mmol)溶解在N,N'-二甲基甲酰胺(200mL)中,并缓慢地依次添加吗啉(5.9mL,68.80mmol)和N,N'-二异丙基乙胺(59.7mL,343.02mmol)。在室温下搅拌16小时后,将反应溶剂减压浓缩,添加0.5N氢氧化钠水溶液,并用乙酸乙酯进行两次提取。将有机层用氯化钠水溶液和水洗涤两次,经无水硫酸镁干燥,过滤。将滤液减压浓缩并通过柱色谱法纯化,得到标题化合物(37.05g,86%)。
MS[M+H]=630(M+1)
步骤D:N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-
(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐的制备
将在步骤C中得到的N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺(5.0g,7.95mmol)溶解在乙酸乙酯(50mL)中,并缓慢添加2N盐酸乙酸乙酯溶液(3.97mL,15.89mmol)。在室温下搅拌30分钟后,将反应溶剂减压浓缩。所生成的粗固体通过用己烷和乙醚研磨进行纯化,得到标题化合物(5.23g,99%)。
MS[M+H]=630(M+1)
1H NMR(500MHz,CD3OD)δ7.49-7.44(m,4H),4.83(m,1H),4.23-4.20(m,1H),3.95-3.91(m,2H),3.79-3.47(m,14H),3.03-3.00(m,1H),2.86-2.82(m,1H),2.73-2.67(m,1H),2.20-2.14(m,1H),1.97(m,1H),1.80-1.62(m,5H),1.50(s,9H),1.44-1.27(m,3H),1.06-1.04(m,9H)
实施例1:对MC1R和MC4R的体外活性的比较实验
通过以下荧光素酶测定、结合亲和力、β-抑制蛋白(β-arrestin)测定和cAMP测定,测量在制备例中得到的N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐(以下称为“受试化合物”)、以及α-MSH、NDP-α-MSH和MTII(美拉诺坦II)——它们已知是黑素皮质素受体激动剂,作为比较物质—对MC1R和MC4R的活性。结果分别在表1至表4中呈现。
实施例1-1:荧光素酶测定
为了测量对于黑皮质素-1受体(MC1R)和黑皮质素-4受体(MC4R)的激动剂能力,建立了持久表达MC1R、MC4R和在CRE(cAMP反应元件)控制下的荧光素酶基因(CRE-LUC)的细胞系。在制备含有MC1R和MC4R基因的哺乳动物细胞表达载体(pCDNA3(Neo))(Invitrogen)后,通过使用Lipofectamine 2000(Invitrogen)以及在cAMP反应元件(CRE)控制下表达荧光素酶基因(CRE-LUC)的载体(pCRE-Luc)(Stratagen)来转化人胚肾(HEK)细胞系。将转化的细胞系(HEK MC1R-Luc和HEK MC4R-Luc)使用含10%热灭活胎牛血清(GIBCO/BRL)的Dulbecco改良Eagles培养基(DMEM)在37℃培养箱中在5% CO2存在下温育24小时。在含有10mL选择培养基(10%热灭活胎牛血清(GIBCO/BRL)、100单位/mL青霉素(GIBCO/BRL)、100单位/mL链霉素(GIBCO/BRL)和800μg/mL遗传霉素(GIBCO/BRL))的Dulbecco改良Eagles培养基(DMEM)存在下,将所述细胞系温育四天。将通过用10mL的新选择培养基替换所述培养基来去除被所述选择培养基杀死的细胞这一过程重复三次,每4天一次。将由最终选择和繁殖的克隆形成的单个集落在显微镜下转移到24孔细胞培养板中,每孔含有1mL选择培养基,并温育4天。将毛喉素(Sigma)处理至最终浓度10μM,然后在37℃培养箱中在5%CO2存在下温育五小时。每孔用50μL的Bright-Glo荧光素酶试剂(Promega)处理并在室温下放置15分钟,然后用光度计(Victor)测量每孔的发光。选择通过用毛喉素处理表现出基值的100倍以上发光的克隆,并将其用于测量各化合物的MC1R和MC4R激动剂能力。
将HEK MC1R-Luc细胞和HEK MC4R-Luc细胞添加到96孔光度计细胞培养板(Costar)的每个孔,至数量为100μL培养基中2.5×104个细胞,然后在37℃培养箱中在6%CO2存在下温育18小时。对在各级浓度下通过上述培养基稀释的MCR激动剂进行处理,以使最终DMSO浓度不超过1%,然后在37℃培养箱中在6% CO2存在下温育五小时。每孔用50μL的Bright-Glo荧光素酶试剂(Promega)处理并在室温下放置五分钟,然后用光度计(Victor)测量每孔的发光。将在各级浓度下稀释的激动剂诱导的发光量换算为相对于通过10μM NDP-α-MSH处理表现出的量的相对%值。EC50表示为诱导各激动剂所能诱导的最大发光量的50%的浓度。测量结果使用统计软件(Prizm)测量。
表1显示了以EC50(nM)单位测量通过上述实验得到的各化合物对MC1R和MC4R的激动剂能力的结果。
[表1]
实施例1-2:结合亲和力
建立表达人重组MC1R的CHO-K1细胞系和表达MC4R的HEK-293细胞系后,收集各细胞系的膜。在96孔细胞培养板中,添加细胞系膜和含有在各级浓度下稀释的MCR激动剂的25mM HEPES-KOH吸附缓冲液(pH 7.0),并进行反应。EC50计算为诱导各激动剂所能诱导的最大结合的50%的浓度,结果在表2中呈现。
[表2]
实施例1-3:β-抑制蛋白测定
建立Pathhunter eXpressβ-抑制蛋白细胞系(U2OS细胞系),其中Prolink(PK)-标签的MC1R和MC4R、以及酶受体(EA)-标签的β-抑制蛋白一起表达。当该细胞系的Mcr-PK部分被激活时,β-抑制蛋白-EA被动员,并且酶受体(EA)和Prolink(PK)——它们是β-半乳糖苷酶片段——相互作用。被激活的酶通过β-半乳糖苷酶活性来水解底物,产生化学发光信号,从而可以测量活性。在Pathhunter eXpressβ-抑制蛋白细胞系(U2OS细胞系)温育后,将所述细胞接种到细胞培养板的每个孔中并在37℃培养箱中在5% CO2存在下温育48小时。温育后,添加5μL用缓冲液稀释5倍的样本,介质物浓度被设置为1%,添加在各级浓度下稀释的MC4R激动剂化合物,随后在37℃下反应90分钟。各激动剂化合物的活性(%)表示为100%×(样本的平均RLU值–介质对照的平均RLU值)/(对照配体的平均最大值–介质对照的平均RLU值),并通过CBIS数据分析套件(ChemInnovation,CA)分析该值。表3显示了以EC50(nM)单位测量通过上述实验获得的各化合物的黑皮质素受体活性能力的结果。
[表3]
实施例1-4:cAMP测定
建立了MC1R和MC4R各自在其中过表达的cAMP Hunter Gs偶联细胞系(CHO-K1细胞系)以便可测量由于激动剂反应引起的细胞内cAMP水平的增加之后,将所述细胞接种到白细胞培养板的每个孔中并在37℃培养箱中在5% CO2存在下温育24小时。温育后,除去培养基,添加15μL的2:1HBBS/10mM HEPES:cAMP XS+Ab试剂。添加5μL用缓冲液稀释5倍的样本后,介质物浓度被设置为1%,添加在各级浓度下稀释的MC4R激动剂化合物,随后在37℃下反应30分钟。各激动剂化合物的活性(%)表示为100%×(样本的平均RLU值–介质对照的平均RLU值)/(最大对照的平均RLU值–介质对照的平均RLU值),并通过CBIS数据分析套件(ChemInnovation,CA)分析该值。表4显示了以EC50(nM)单位测量通过上述实验获得的化合物的黑皮质素受体激动剂能力的结果。
[表4]
在表1至4中,EC50值越低,对相应受体的激动能力越好。对MC4R的特异性可以通过计算MC1R的EC50与MC4R的EC50的比率来确认,该比率的值大,表明对MC4R的选择性出色。根据本发明的受试化合物的上述比率从至少5到最大37.98。由此确认,本发明的受试化合物表现出对参与体内能量代谢和体重控制的MC4R相比对参与皮肤色素沉着的MC1R的优异选择性。
实施例2:皮肤中药物浓度和分布的测量
关于皮肤色素沉着——这是MC4R激动剂的脱靶效应,在缺乏瘦素受体的db/db小鼠模型中,通过测量重复施用后皮肤和血浆中的药物浓度来评价药物的分布和蓄积。结果在图1中呈现。
作为比较物质,使用司美诺肽(setmelanotide)(Ac-RC[dA]H[dF]RWC-NH2(二硫化物)(AcOH盐))——这是一种MC4R激动剂肽,对MC4R的选择性比MC1R低,并且据报道在临床试验中显示出皮肤色素沉着(Clement等,自然医学(Nature Medicine),2018)。
从图1可以看出,确认了本发明的受试化合物在重复施用后没有在皮肤中相对蓄积。
实施例3:皮肤色素沉着的测量
为了确认皮肤色素沉着——这是MC4R激动剂的一种脱靶效应——发生的可能性,在猴子的重复毒性试验中测量了皮肤和皮肤毛发中的色素沉着模式,结果在图2中呈现。
从图2可以看出,在本发明的受试化合物的情况下,确认了当重复施用2周时,皮肤和皮肤毛发上没有出现色素沉着。
Claims (18)
1.一种用于预防或治疗黑皮质素受体相关疾病的药物,所述药物对黑皮质素-4受体具有选择性激动效应,其包含治疗有效量的下式1的化合物或其可药用盐:
[式1]
其中R1是C2-C5烷基。
2.根据权利要求1所述的药物,其中所述式1的化合物是下式2的N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺:
[式2]
3.根据权利要求1所述的药物,其中所述可药用盐选自盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸。
4.根据权利要求1所述的药物,其中所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率为2以上。
5.根据权利要求4所述的药物,其中所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率为5以上。
6.根据权利要求1所述的药物,其中所述黑皮质素受体相关疾病选自肥胖症、糖尿病、炎症和勃起功能障碍。
7.根据权利要求6所述的药物,其中所述黑皮质素受体相关疾病是肥胖症。
8.根据权利要求1所述的药物,其特征在于减少色素沉着。
9.根据权利要求1所述的药物,所述药物是口服制剂。
10.一种用于预防或治疗黑皮质素受体相关疾病的药物组合物,所述药物组合物对黑皮质素-4受体具有选择性激动效应,其包含治疗有效量的下式1的化合物或其可药用盐,以及可药用载体:
[式1]
其中R1是C2-C5烷基。
11.根据权利要求10所述的药物组合物,其中所述式1的化合物是下式2的N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺:
[式2]
12.根据权利要求10所述的药物组合物,其中所述可药用盐选自盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸。
13.根据权利要求10所述的药物组合物,其中所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率为2以上。
14.根据权利要求13所述的药物组合物,其中所述式1的化合物或其可药用盐对黑皮质素-4受体的选择性与对黑皮质素-1受体的比率为5以上。
15.根据权利要求10所述的药物组合物,其中所述黑皮质素受体相关疾病选自肥胖症、糖尿病、炎症和勃起功能障碍。
16.根据权利要求15所述的药物组合物,其中所述黑皮质素受体相关疾病是肥胖症。
17.根据权利要求10所述的药物组合物,其特征在于减少色素沉着。
18.根据权利要求10所述的药物组合物,所述药物组合物是口服制剂。
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