CN115282152A - 用于增强PPARγ表现及核转位之化合物及其医疗用途 - Google Patents
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Abstract
本发明涉及用于增强PPARγ表现及核转位之化合物及其医疗用途。本发明系关于一种新颖类型之PPARγ调节剂,其具有嘧啶并[5,4‑d]嘧啶主要结构。该PPARγ调节剂可以增强PPARγ在细胞中之表现及核转位。本发明亦关于一种医药组合物,其包含本发明之PPARγ调节剂,该PPARγ调节剂囊封于医药学上可接受之穿透细胞之药物传递系统中,使得其可以直接传递至细胞中。因此,本发明提供一种预防或治疗PPARγ相关病症或病况之方法,该方法包含向有需要之个体投与治疗有效量之本发明之PPARγ调节剂或本发明之医药组合物。
Description
本申请是申请日为2016年1月27日、申请号为“201680003479.1”、名称为“用于增强PPARγ表现及核转位之化合物及其医疗用途”的发明专利申请的分案申请。
技术领域
本发明提供一种增强PPARγ之表现及核转位之方法及相关医疗用途。
先前技术
在过去十年间,在核受体家族中,过氧化体增殖物活化受体(PPAR)一直受到关注。PPAR为藉由其配体活化之核转录因子且充当代谢症候群中之关键调控因子(Guan,Y.J.Am.Soc.Nephrol,2004,15,2801-2815)。因此,PPAR在某些疾病之成因、发展及控制方面起重要作用,该等疾病诸如胰岛素抗性、葡萄糖耐量异常、II型糖尿病、肥胖、高脂质血症、高血压、血管心病、动脉粥样硬化等。
PPAR分为三个亚型:PPARα、PPARδ及PPARγ,其藉由结合至基因之特定DNA 序列来调控基因之表现(Berger,J.等人,The Journal of Biological Chemistry,1999,274(10), 6718-6725)。PPARα主要在肝脏、心脏、肠道、肾脏及巨噬细胞中表现,且在活化之后,可以增加脂肪酸之代谢,缓解巨噬细胞中之炎症反应,且减少低密度脂蛋白胆固醇; PPARγ在脂肪细胞、胎盘瘤及其他组织中表现,且在活化之后,不仅可以降低血糖水平及增加胰岛素敏感性,而且在脂质代谢、细胞激素拮抗、消炎、免疫调控、血压调控等方面起到关键作用(Kasuga,J.等人,Bioorg.Med.Chem.2007,15,5177-5190;US 8822519 B2)。
PPARγ含有三种同功异型物γ1、γ2及γ3,经由选择性剪接自相同基因转录且展示不同的组织特异性。PPARγ1及γ3之长度相同;然而,γ2含有具有28个胺基酸之额外 N端区域。所有PPARγ同功异型物均可以藉由抗糖尿病剂噻唑啶二酮(TZD)活化。TZD 藉由靶向核中之PPARγ起作用且由此提高胰岛素抗性,主要提高脂肪组织中之胰岛素抗性,且在肝脏及骨胳肌中以PPARγ表现较低之次要方式起作用。PPARγ对于脂肪细胞分化而言至关重要,因为PPARγ可以调节脂肪组织中之基因表现。配体诱导之活化引起脂质代谢、脂质吸收及胰岛素作用增强,且脂肪分解及游离脂肪酸(FFA)释放减弱。因此,循环中之FFA减少且脂肪组织中之脂质含量增加。已经提出,PPARγ促效剂可以改善高血糖症,其藉由使脂质远离肝脏及肌肉重新分布,对高度FFA诱导之胰岛素抗性作出反应。自内脏脂肪组织排出至皮下脂肪中之脂肪酸引起肝脏之葡萄糖产量减少且葡萄糖稳态改善。PPARγ配体亦与脂肪组织中脂肪细胞激素合成之调控相关,诸如肿瘤坏死因子-α(TNF-α)、介白素-6(IL-6)、抵抗素、瘦素、脂联素,其影响胰岛素作用。TNF-α、 IL-6及抵抗素会导致胰岛素抗性,然而瘦素及脂联素可以提高胰岛素敏感性。另外,在胰岛素信号转导受到抑制的肥胖及胰岛素抗性啮齿动物之脂肪组织中,PPARγ使诸如 TNF-α之促炎性细胞激素及巨噬细胞之趋化因子的表现减少且从而使其累积。因此, PPARγ促效剂有助于消炎。因此,PPARγ活化将提高肝脏及骨骼肌中之胰岛素敏感性且缓解高血糖症(Peng,Yi-Hui,Structure based drugdesign of peroxisome proliferator-activated receptor(PPAR)agonists,DoctoralDissertation,National Tsing Hua University,2010)。
诸多疾病与PPARγ之调控相关。已在糖尿病及以胰岛素抗性为特征之其他疾病之治疗中使用PPARγ促效剂。然而,除糖尿病以外,研究人员亦发现,PPARγ涉及多个调控机制且为用于治疗各种疾病之潜在目标,该等疾病包括:动脉粥样硬化、血脂异常、肥胖及症候群X、心血管疾病、炎症及神经学疾病、阿兹海默氏病(Alzheimer's disease)、多发性硬化症、帕金森氏病(Parkinson's disease)、缺血性卒中、脊髓损伤、牛皮癣性关节炎及慢性阻塞性肺病。据报导,PPARγ亦与眼病、病毒感染、肾病、多囊卵巢疾病、炎症性肠病、哮喘、骨骼疾病、衰老及长寿、药物代谢、伤口愈合、痤疮及线粒体功能障碍病相关(Kumar A,Hasamnis A.A clinical update on peroxisome proliferator-activatedreceptors.Syst Rev Pharm 2010;1:175-81)。
据报导,PPAR具有炎症调控作用。特定言之,其可以在组织损伤之后调控炎症反应。根据对卒中之研究,在诸如器官移植、区室症候群、心肌梗塞、卒中及出血性、创伤性或败血性休克的广泛范围之病况中,缺血性/再灌注(I/R)损伤代表具有重大临床意义的具有挑战性的病理生理病况。已经显示,组织缺血连同后续再灌注一起可触发整个发炎级联反应事件,该等事件若早期未遭到抵制,则将导致细胞坏死,导致受侵袭之器官中组织不可逆损伤。近年来的研究工作已经有愈来愈多的证据表明,PPAR代表此类炎症反应之主要调控因子;据显示,PPAR活化可以限制炎症且发挥对抗缺血性/再灌注损伤之多种有利作用。因此,已提出将靶向PPAR之药理学药剂作为用于治疗I/R之潜在疗法(Neher MD,Weckbach S,Huber-Lang MS,Stahel PF.New insights into the role of peroxisomeproliferator-activated receptors in regulating the inflammatory responseafter tissue injury.PPAR Res.2012;2012:728461)。
类似于其在创伤性中枢神经系统(CNS)损伤方面之作用,可以证明PPAR组织表现与I/R损伤之间的关联性较强。在肾脏I/R中,内皮细胞、间质细胞及肾脏之集尿管中之PPARγ表现剧烈增加,在再灌注之后1.5至5小时达到峰值。在大鼠中,在局灶性大脑缺血之后,在皮质梗塞周围区域中侦测到PPARγ之类似上调。有趣的是,Lee及同事 (C.H.Lee,O.K.Park,K.Y.Yoo等人,「The role of peroxisome proliferator-activated receptorγ,and effects of its agonist,rosiglitazone,on transient cerebral ischemicdamage」, Journal of the Neurological Sciences,第300卷,第1-2期,第120-129页,2011)最近在短暂性大脑缺血模型中发现,海马区中之PPARγ免疫反应性与小神经胶质细胞共存,表明在缺血性脑中小神经胶质之高功能状态。
近年来,各种器官中之I/R损伤之动物研究已揭示出PPAR在缺血性及再灌注之后减少或甚至预防组织损伤及器官功能障碍方面的关键作用。因此,已在实验I/R模型中对各种天然及合成PPAR促效剂进行测试且其显示出可显著改善I/R损伤之结果。藉由 PPAR配体进行组织保护之机制认为是多因素的,因为此等促效剂可以与IR诱导之发炎级联反应之可变参数相互作用且抑制损伤进程途中之多个目标。已提出之作用机制包括:(i)减少内皮细胞上如ICAM-1及p-选择素之黏着分子的表现,(ii)降低血管渗透性且抑制水肿形成,(iii)抑制如细胞激素及趋化因子之促炎性介体之释放,(iv)减少如嗜中性白血球之炎症细胞的活化,(v)减少活性含氧物之形成,(vi)遏制细胞凋亡及坏死,及(vii) 抑制血小板凝集及血栓形成。类似于CNS损伤,此等消炎作用中之大多数藉由PPAR诱导遏制转录因子(主要为NF-κB)且随后抑制促炎性基因转录来起始。除去PPAR活化对 I/R中之炎症反应的已提及之一般作用以外,亦已描述PPAR促效剂在不同器官系统中之众多组织特异性影响。
肾脏缺血为急性肾衰竭之主要原因,急性肾衰竭因为低氧组织之后续再灌注可能造成额外损伤这一事实而变得复杂。所有三种PPAR同功异型物PPARα、PPARβ/δ及PPARγ之促效剂均可显著减少经历肾脏缺血及再灌注之小鼠的组织损伤。此种肾脏保护作用反映在以下方面:皮质及髓质坏死减少,肾脏损伤之组织学病征减少,且最后肾脏功能剧烈增加且血清肌酸酐及脲氮含量降低。此等有利特性之根本机制可能由PPAR在肾脏组织中诱导脂肪酸β-氧化酶组成;近端小管中表现PPARα之转殖基因小鼠已显示所施加之脂肪酸氧化增加且受到保护不会发生I/R诱发之肾衰竭。
在肺移植之后,在20%之患者中仍会出现肺部I/R损伤,且肺部I/R损伤仍为移植后第一个月内死亡的主要原因(R.C.King,O.A.R.Binns,F.Rodriguez等人, 「Reperfusioninjury significantly impacts clinical outcome after pulmonarytransplantation」, Annals of Thoracic Surgery,第69卷,第6期,第1681-1685页,2000)。在缺血之前施用合成PPARγ配体吡格列酮(pioglitazone)或天然PPARγ促效剂15-脱氧-Δ12,14-前列腺素 J2(15d-PGJ2)可以缓解大鼠之肺部I/R损伤。Okada等人之最新研究(M.Okada,S.F.Yan 及D.J.Pinsky,「Peroxisome proliferator-activated receptor-γ(PPAR-γ)activation suppresses ischemic induction of Egr-1and itsinflammatory gene targets」,FASEB Journal, 第16卷,第14期,第1861-1868页,2002)指出,PPARγ活化可遏制锌指转录因子早期生长反应基因-1(Egr-1)之活化,后者在缺血性血管中之炎症反应中具有关键作用。因此,由于PPARγ活化,所以诸如介白素-1β之Egr-1目标基因之诱导得以防止,IR相关之白血球停滞减少,且总存活率提高。
肠及胃I/R损伤为由腹部动脉瘤、急性肠系膜缺血、小肠移植或休克造成的严重临床病况。在肠I/R之啮齿动物模型中,PPAR促效剂之所有三种同型均展示出与I/R诱发之死亡率降低相关之深远的消炎、抗氧化及抗凋亡作用。类似地,吡格列酮及罗格列酮(rosiglitazone)可遏制胃I/R大鼠中之胃黏膜糜烂及损伤。另外,在肠道I/R之后的早期肠内营养之有利作用可能与PPAR诱导有关。据报导,营养组分麸酰胺酸可藉由活化 PPARγ发挥肠道保护作用。
缺血性脑血管疾病代表第三大死亡原因且为神经功能障碍及失能之主要原因之一。各种研究表明,PPAR促效剂可以预防局灶性缺血及整体缺血或降低其严重程度。在人类中,当用袪脂乙酯制剂(fibrate)及PPARα促效剂吉非罗齐(gemfibrozil)治疗患有冠心病且HDL及LDL胆固醇值低之男性时,卒中发生率降低。在短暂性缺血性脑损伤之啮齿动物中施用PPARα、PPARβ/δ及PPARγ配体促使神经元损伤显著减弱且梗塞体积减小,脑血流量增加,且神经结果参数改善。当在缺血之前、在脑梗塞时或在缺血之后两小时功效时间窗之后不久,对动物进行预防性治疗时,观察到此类神经保护。相比于短暂性缺血,当血流永久性中断且无后续再灌注时,PPARγ活化无法减小梗塞体积。此等发现支持以下论证:PPARγ之神经保护作用对再灌注期间发生之事件具有特异性。
总体而言,各种研究提供证据表明,PPAR之配体藉由干扰I/R诱导之发炎级联反应之多个目标,引起不同器官中之I/R损伤实质上减少。
基于PPARγ之PPAR促效剂具有消炎、抗氧化及抗MMP特性且可以给细胞提供保护。因此,除急性缺血性疾病以外,此类PPARγ促效剂亦尤其适合于治疗急性器官损伤,包括急性肺损伤、急性肾损伤、急性肝损伤、急性心肌炎、急性心肌梗塞、急性胃肠损伤及急性腹膜炎。另外,归因于治疗多种器官损伤之能力,PPARγ促效剂可以治疗在临床上造成多种器官损伤之疾病,诸如败血症及心肾症候群。藉由修改其剂型及载剂以延长药物之半衰期及控制释放特性,PPARγ促效剂可以用于治疗慢性炎症性疾病。
临床上可获得的PPARγ促效剂包括用于降低血糖之药剂,诸如TZD;及用于降低血脂之药剂,诸如士他汀(statin)。
TZD为有效的口服降血糖药(参见图1)。药理学作用已经证实为活化PPARγ。然而,TZD具有诸多副作用。举例而言,曲格列酮(troglitazone)引起肝炎且自2000年起已经下架;法国及德国已经暂停使用吡格列酮,因为有报导指出,此类药物可能增加膀胱癌之风险;且罗格列酮由于心血管疾病之风险增加,已自2010起在英国及欧盟暂停使用。
目前正在实验之PPARγ促效剂包括萘格列酮(netoglitazone)及利格列酮(rivoglitazone)。较早研发但尚未得到批准之药物包括环格列酮(ciglitazone)。此等药物之主要化学骨架仍为噻唑啶二酮,且因此仍可能增加肝炎、膀胱癌及心血管疾病之风险。
士他汀为用于降低血脂含量之医药试剂(参见图2)。士他汀之药理学作用主要为抑制HMG-CoA。士他汀之特征在于基于目标酶受质HMG-CoA之主链的化学改质结构。士他汀包括洛伐他汀(lovastatin)、普伐他汀(pravastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、罗素他汀(rosuvastatin)、阿托伐他汀(atorvastatin)及匹伐他汀(pitavastatin)。据报导,士他汀可以活化PPAR。
其他PPAR双重(α及γ)促效药物包括替格列扎(tesaglitazar)、拉格列扎(ragaglitazar)、那格列扎(naveglitazar)及莫格列扎(muraglitazar)(参见图3)。其用于治疗2型糖尿病及血脂异常。然而,经US FDA鉴别,此等药物存在毒性问题。
鉴于以上内容,当前可获得的调节PPAR活性或表现之药物主要为具有噻唑啶二酮主链或HMG-CoA类似物之彼等药物。临床上安全且有效之PPARγ促效剂的选择有限。当前可获得的PPARγ促效剂仍会带来潜在的副作用风险。需要提供可以用于治疗PPARγ相关病症或病况之新颖PPARγ调节剂。
US 3,031,450揭示经取代之嘧啶并[5,4-d]嘧啶化合物,其具有下式:
其中取代基R1至R4中之两者、三者或所有四者为选自由以下各者组成之群的碱性部分:胺基、低碳数烷基胺基、烷基部分具有1至12个碳原子之二烷基胺基、单-(羟基 -低碳数烷基)胺基、二(羟基-低碳数烷基)-胺基、烷基部分具有1至12个碳原子之(羟基 -低碳数烷基)-烷基胺基、(低碳数烷氧基-低碳数烷基)-胺基、低碳数烯基-胺基、环己基- 胺基、卤苯基-胺基、硝基苯基-胺基、(低碳数烷氧基-苯基)胺基、[(二低碳数烷基-胺基)- 苯基]-胺基、苯甲基胺基、半卡肼基、肼基、胍基、伸乙基亚胺基、哌啶基、低碳数烷基-哌啶基、低碳数烷氧基-哌啶基、羟基-哌啶基、吡咯啶基、低碳数烷基-吡咯啶基、低碳数烷氧基-吡咯啶基、羟基-吡咯啶基、吗啉基、低碳数烷基-吗啉基、低碳数烷氧基- 吗啉基、羟基-吗啉基、四氢吡啶基、低碳数烷基-四氢吡啶基、低碳数烷氧基-四氢吡啶基、羟基四氢吡啶基、六亚甲基亚胺基、低碳数烷基-六亚甲基亚胺基、低碳数烷氧基- 六亚甲基亚胺基、羟基-六亚甲基亚胺基、四氢喹啉基、低碳数烷基-四氢喹啉基、低碳数烷氧基-四氢喹啉基、羟基-四氢喹啉基、哌嗪基、低碳数烷基哌嗪基、低碳数烷氧基- 哌嗪基、羟基-哌嗪基及N'-低碳数烷基哌嗪基,且其余的取代基R1至R4选自由以下各者组成之群:氢、卤素、羟基、巯基、低碳数烷基、苯基、低碳数烷氧基、二低碳数烷基-胺基-低碳数烷氧基及低碳数烷基-硫基、苯基-硫基、苯甲基-硫基、低碳数烷氧基-低碳数烷氧基,其对人体无害之碱金属盐及其对人体无害之酸加成盐。在此等化合物中,双嘧达莫尤其受关注。
双嘧达莫为经取代之嘧啶并[5,4-d]嘧啶化合物,其具有以下结构式(I):
已知,双嘧达莫可以抑制磷酸二酯酶(PDE)且抑制腺苷之吸收。然而,动物研究揭示,高剂量为治疗学上不可接受的。先前研究发现,高剂量双嘧达莫将造成腺苷在肾组织中累积且因此增加血管收缩之副作用且减小肾血流量,尤其在诸如猫及狗之小型哺乳动物中(Arend LJ,Thompson CI及Spielman WS.Dipyridamole decreases glomerularfiltration in the sodium-depleted dog.Evidence for mediation by intrarenaladenosine.Circ Res 56:242-251,1985;Thompson CI,Sparks HV及Spielman WS.Renalhandling and production of plasma and urinary adenosine.Am J Physiol RenalFluid Electrolyte Physiol 248:F545-F551,1985;Arend LJ,Bakris GL,Burnett JC JrMegerian C及Spielman WS. Role for intrarenal adenosine in the renalhemodynamic response to contrast media.J Lab Clin Med 110:406-411,1987;Katholi RE,Taylor GJ,McCann WP,Woods WT Jr,Womack KA,McCoy CD,Katholi CR,Moses HW,Mishkel GJ及Lucore CL.Nephrotoxicity from contrast media:attenuationwith theophylline.Radiology 195:17-22,1995)。另外,Lin等人 (Lin JJ,Churchill PC及Bidani AK.The effect of dipyridamole on the initiation phase ofpostischemic acute renal failure in rats.Can J Physiol Pharmacol 65:1491-1495,1987)揭示,投与双嘧达莫将使正遭受缺血后急性肾衰竭之小鼠的病况加重。因此,双嘧达莫视为不合适用于小型哺乳动物中。如核子医学中在心动描记法中所用的静脉内注射双嘧达莫来诱导血管扩张举例说明,短期内投与大量双嘧达莫将造成低血压。因此,需要一种降低临床治疗中双嘧达莫之治疗剂量的方法。
发明內容
在本发明中发现,某些经取代之嘧啶并[5,4-d]嘧啶化合物(诸如双嘧达莫)能够增强 PPARγ之表现及核转位。因此,本发明提供一种新颖类型的具有嘧啶并[5,4-d]嘧啶主要结构之PPARγ调节剂及使用此类PPARγ调节剂来预防或治疗PPARγ相关病症或病况的方法,该等PPARγ相关病症或病况诸如胰岛素抗性、葡萄糖耐量异常、II型糖尿病、肥胖、高脂质血症、高血压、血管心病、动脉粥样硬化、血脂异常、肥胖及症候群X、心血管疾病、炎症及神经学疾病、阿兹海默氏病、多发性硬化症、帕金森氏病、缺血性卒中、脊髓损伤、牛皮癣性关节炎、慢性阻塞性肺病、眼病、病毒感染、多囊卵巢疾病、炎症性肠病、哮喘、骨骼疾病、衰老及长寿、药物代谢、伤口愈合、痤疮、线粒体功能障碍病、缺血性卒中、肾病、肝病、肺病、心血管疾病、自身免疫病症及全身性炎症反应症候群(败血症)。本发明亦关于一种增加PPARγ之表现及核转位的方法。
在一实施例中,本发明系关于一种预防或治疗PPARγ相关病症或病况之方法,该方法包含向有需要之个体投与治疗有效量之PPARγ调节剂,较佳式I化合物:
其中R1、R2、R3及R4中之每一者独立地选自由杂环基及二(羟烷基)胺基组成之群,
或其医药学上可接受之盐。
在另一实施例中,本发明提供一种预防或治疗PPARγ相关疾病之方法,该方法包含向有需要之个体投与医药组合物,该医药组合物包含治疗有效量之式I化合物或其医药学上可接受之盐,其囊封在医药学上可接受之穿透细胞之药物传递系统中。
本发明亦关于式I化合物或其医药学上可接受之盐之用途,其用于制造用于预防或治疗PPARγ相关病症或病况之药物。在一较佳实施例中,该药物包含囊封于医药学上可接受之穿透细胞之药物传递系统中的式I化合物或其医药学上可接受之盐。
本发明进一步关于一种用于预防或治疗PPARγ相关疾病之医药组合物,该医药组合物包含治疗有效量之式I化合物或其医药学上可接受之盐,其囊封于医药学上可接受之穿透细胞之药物传递系统中。在一较佳实施例中,该化合物为双嘧达莫且穿透细胞之药物传递系统为脂质体。
在以下部分中详细描述本发明。本发明之其他特征、目的及优势可以在本发明之实施方式及权利要求书中容易地找到。
图式简单说明
图1显示噻唑啶二酮(TZD)药物之化学结构。
图2显示士他汀药物之化学结构。
图3显示PPAR双重促效剂(α及γ)药物之化学结构。
图4a及图4b为展示双嘧达莫在以游离形式或在穿透细胞之药物传递系统中传递时之作用的方案。
图5显示脂质体之直径资料。
图6显示患有LPS诱发之败血症之小鼠在治疗后的存活率。
图7a及图7b显示PPARγ在经双嘧达莫(游离形式)及双嘧达莫脂质体处理之HEK293 细胞中之表现。
图8显示经双嘧达莫(游离形式)及双嘧达莫脂质体处理之HEK293细胞的活力。
图9显示治疗后之肝脏标记(AST、ALT)及肾脏标记(BUN、肌酸酐)。
图10显示肝脏组织在治疗后之HE染色。
图11显示肺组织在治疗后之HE染色。
图12a及图12b分别显示在治疗之后,肾脏及肝脏中之PPARγ表现的西方墨点分析。
图13a及图13b显示双嘧达莫及双嘧达莫脂质体对血压之影响。
实施方式
除非本文中另外定义,否则结合本发明使用之科学与技术术语应具有一般技术者通常理解之含义。术语之含义及范畴应为清楚的;然而,在任何潜在不明确性之情况下,本文中提供之定义优先于任何字典或外部定义。
除非另外指明,否则如根据本发明采用之以下术语应理解为具有以下含义。
如本文中所用之术语「PPARγ调节剂」系指可以调节PPARγ之表现或核转位的药剂。
如本文中所用之术语「烷基」系指具有1至6个碳原子、尤其1至4个碳基之饱和直链或分支链烃基,例如甲基、乙基、丙基、1-甲基乙基、丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、 1-乙基丙基、己基、1,1-二甲基丙基、1,2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2- 三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基。C1-C4烷基意谓例如甲基、乙基、丙基、1-甲基乙基、丁基、1-甲基丙基、2-甲基丙基或1,1-二甲基乙基。
如本文中所用之术语「杂环基」系指具有5至8个环成员之单环基团,其中在各情况下,此等环成员中之1、2、3或4个为彼此独立地选自由氧、氮及硫组成之群的杂原子。
如本文中所用之术语「预防(preventing)」或「预防(prevention)」系指延迟易得病个体之症状的发作或降低疾病之发生率。
如本文中所用之术语「治疗(treating)」或「治疗(treatment)」表示减少及/或改善易得病个体之症状或提高患有某些致死性病症或病况之个体的存活率。
如本文中所用之术语「PPARγ相关病症或病况」表示PPARγ之调节有利的病症或病况。举例而言,此类病症或病况包括胰岛素抗性、葡萄糖耐量异常、II型糖尿病、肥胖、高脂质血症、高血压、血管心病、动脉粥样硬化、血脂异常、肥胖及症候群X、心血管疾病、炎症及神经学疾病、阿兹海默氏病、多发性硬化症、帕金森氏病、缺血性卒中、脊髓损伤、牛皮癣性关节炎、慢性阻塞性肺病、眼病、病毒感染、多囊卵巢疾病、炎症性肠病、哮喘、骨骼疾病、衰老及长寿、药物代谢、伤口愈合、痤疮、线粒体功能障碍病、缺血性卒中、肾病、肝病、肺病、心血管疾病、自身免疫病症、全身性炎症反应症候群(败血症)及其类似者。
如本文中所用之术语「个体」表示动物,尤其哺乳动物。在一个较佳实施例中,术语「个体」表示人类。在另一较佳实施例中,术语「个体」表示伴侣动物,诸如猫及狗。
如本文中所用之术语「治疗有效量」系指单独使用或与用于治疗PPARγ相关病症或病况之其他治疗/药物组合使用的活性成分之显示治疗功效之量。
术语「载剂」、「医药学上可接受之载剂」、「穿透细胞之药物传递系统」或「医药学上可接受之穿透细胞之药物传递系统」系指可以囊封活性医药成分之粒子。适合于本发明之穿透细胞之药物传递系统的实例包括囊泡、聚合物囊泡、奈米粒子、脂质体、奈米悬浮粒子、固体脂质奈米粒子、磁性奈米载剂、微胞、大分子结合物、微粒药物载剂及其类似者。
除非上下文另外需要,否则单数术语应包括复数,且复数术语应包括单数。
本发明之发明人意外发现,具有嘧啶并[5,4-d]嘧啶结构之化合物可以增强PPARγ之表现及核转位,且因此可以充当新颖类型之PPARγ调节剂。在一较佳实施例中,嘧啶并[5,4-d]嘧啶化合物为双嘧达莫。
因此,本发明提供一种预防或治疗PPARγ相关病症或病况之方法,该方法包含向有需要之个体投与治疗有效量之式(I)化合物:
其中R1、R2、R3及R4中之每一者独立地选自由杂环基及二(羟烷基)胺基组成之群,
或其医药学上可接受之盐。
在一实施例中,R1及R3为杂环基,较佳哌啶基,且R2及R4为二(羟烷基)胺基,较佳N,N-二(羟乙基)胺基。
在一较佳实施例中,该化合物为双嘧达莫。
在另一实施例中,该化合物囊封于穿透细胞之药物传递系统中,诸如囊泡、聚合物囊泡、奈米粒子、脂质体、奈米悬浮粒子、固体脂质奈米粒子、磁性奈米载剂、微胞、大分子结合物或微粒药物载剂。
在一较佳实施例中,穿透细胞之药物传递系统为脂质体。在另一实施例中,脂质体之直径在约100-300nm、较佳约150-280nm、更佳约180-270nm之范围内。
此项技术中已知,当双嘧达莫以游离形式投与时,其结合至细胞膜上之受体且活化信号传导路径,产生不利的副作用。本发明人发现,双嘧达莫可以促进PPARγ表现及核转位且从而活化下游信号传导路径。PPARγ信号传导路径之活化可以有助于治疗已知与PPARγ不活化相关之诸多疾病。
图4a显示,若双嘧达莫以游离形式投与,则其主要在细胞外部起作用且将促进腺苷累积,腺苷累积将导致血液动力学功能障碍及血压改变。图4b显示,双嘧达莫在细胞内部可以活化PPARγ信号传导路径,其可以抑制由LPS导致之肾亏损。在此情况下,双嘧达莫在细胞外部之不利作用可以得以避免。在以下实例中,本发明证实,藉由将双嘧达莫直接传递至细胞中,可以避免结合至细胞膜上之受体,从而减少由腺苷累积导致之副作用,诸如氧化应激及血管收缩。
奈米粒子药物载剂进入细胞之方式不同于习知药物之进入方式。习知药物藉由扩散进入细胞,扩散为剂量依赖性的。亦即,血液中之药物浓度愈高,细胞中之药物浓度愈高,且药物仅可以进入细胞质。奈米粒子药物传递系统经由内饮作用由细胞吸收且在进入细胞之后为趋溶酶体的。在注射后之初始阶段,奈米粒子药物传递系统之浓度以时间相依方式增加。
内饮作用为将细胞外材料并入细胞中之过程。此过程可以分成三类,亦即吞噬作用、胞饮作用及受体介导之内饮作用。吞噬作用仅发生在专门的细胞中。此等细胞在受到细胞外材料刺激时增殖且聚集,且将其吞噬至细胞中之溶酶体中进行降解。此过程发生在免疫系统之巨噬细胞及嗜中性白血球中。胞饮作用为将细胞外流体及其中之分子经由细胞膜之内陷内化形成凹穴,该凹穴随后夹断进入细胞中形成小泡的过程。该小泡随后行进至胞溶质中且与诸如内体及溶酶体之其他小泡融合。
视载剂之结构而定,胞饮作用可以分成两类:流体相胞饮及吸附胞饮。若载剂不含与细胞相互作用之官能基,则细胞将藉由流体相胞饮吞噬药物载剂。此过程缓慢且视细胞膜周围之载剂浓度而定。当载剂具有疏水性基团或带正电荷时,发生吸附胞饮。此类载剂将由细胞膜物理吸附且提高细胞之吞噬能力。以上两类内饮作用为非特异性过程且不适合将药物传递至其目标。仅可以经由增强渗透及滞留(EPR)在某些癌症组织中达成靶向。
受体介导之内饮作用为细胞藉以藉由使含有某类蛋白质之质膜小泡向内出芽来吸收分子(内饮作用)的过程,该等蛋白质具有对待吸收之分子具有特异性之受体位点。在药物载剂结合至细胞上之受体之后,内源信号将触发细胞膜形成被覆孔。被覆孔之表面积相当于细胞膜之1%至2%。被覆孔将自细胞膜脱落且进入细胞中,在细胞中形成被覆小泡,且随后形成内体且以跳跃运动移动至细胞内。内体为包含微管及小泡之复杂结构。小泡可以与高基体(Golgi)融合。由于质子泵(ATP酶),内体通常变成酸性。内体随后将与溶酶体融合形成次级溶酶体。
细胞膜为将疗法有效传递至线粒体、细胞质或细胞核中之目标位点中所要克服的障碍。疏水性磷脂为细胞膜中阻碍疗法转运之主要组分。因此,已研发出诸如脂质体、奈米粒子及病毒载体之各种传递系统来跨膜转移小分子、肽、蛋白质及寡核苷酸。此类药物传递方式在本文中称为穿透细胞之药物传递系统。
关于疗法之细胞内传递,已探索出多种穿透细胞之药物传递系统(脂质体、细胞穿透肽、阳离子聚合物结合物及聚合物奈米粒子)。其需要经调适以跨越一系列膜障碍,以便达至细胞中之药物作用位点。在此过程期间,大部分药物分子将在各连续障碍处损失。此等障碍包括药物-载剂藉由内饮作用发生细胞结合及内化;药物或药物-载剂细胞内移行且释放至细胞质中;药物或药物-载剂细胞质转位至细胞核或任何其他细胞器;及细胞核/细胞器吸收。细胞含有若干具有特定功能之细胞内细胞器。预期将疗法细胞内靶向此等特异性细胞器不仅显著增强治疗功效,而且减少非特异性效应且因此降低毒性。因此,对使用不同的穿透细胞之药物传递系统达成疗法之细胞内目标特异性传递存在浓厚的兴趣。
有助于药物之内饮作用的穿透细胞之药物传递系统包括奈米大小之聚合物载剂及脂质体。视药物特性及制备方法而定,奈米大小之药物载剂可以分成奈米粒子、奈米脂质体、奈米悬浮粒子、固体脂质奈米粒子、磁性奈米载剂及其类似者。
除上文所提及之穿透细胞之药物传递系统以外,亦可以使用细胞穿透肽(CPP)、生物可降解奈米粒子及病毒载体作为用于增强药物渗透至细胞中之传递系统。
RGD肽之细胞内化主要由质膜处之网格蛋白、胞膜窖及巨胞饮内饮路径介导。作为质膜处之内饮转运之主要效应子之一,网格蛋白介导之内饮作用参与以下过程:经由配体之受体依赖性内饮作用,将大型细胞外粒子转运至细胞中。肽内化之替代性途径为经由胞膜窖介导之内饮作用。细胞膜中之脂质筏有助于经由此路径之内化;此等筏含有小窝蛋白-1蛋白质,该等蛋白质形成内体,该等内体随后在整个细胞中转运。相比之下,巨胞饮作用涉及小型细胞外粒子至细胞中之流体相内饮作用。已证明,αVβ3整合素可以经由网格蛋白及胞膜窖依赖性内饮路径作为整合素转换调控之一部分得以内化。因此,对于穿透细胞之药物传递系统而言,RGD肽为理想的(Cam A,Sivaguru M,Gonzalez de Mejia E.Endocyticmechanism of internalization of dietary peptide lunasin into macrophages ininflammatory condition associated with cardiovascular disease.PLoS One. 2013年9月5日;8(9):e72115)。
因为细胞膜构成大尺寸亲水性蛋白质、肽及寡核苷酸之细胞内传递的主要障碍,所以已探索出细胞穿透肽(CPP)来克服此障碍。此等CPP可以将与其连接之分子或胶态药物传递系统跨越细胞膜运送至细胞质中且运送至细胞核。CPP之特征系归因于存在9-16 个阳离子胺基酸残基之延伸段;最常研究之CPP包括HIV-1转活化转录活化剂(TAT)肽、 HSV VP-22(单纯疱疹病毒1型转录因子)肽及穿膜肽。已提出若干理论来确定此等CPP 藉以进入细胞的准确机制。举例而言,已经显示,TAT穿透细胞膜与受体及转运体无关,且已表明系藉由使磷脂双层去稳定化形成反微胞而进入细胞。TAT偶合之主要益处在于:随着分子之有效传递,偶合分子之生物活性得以保存,且待转运之分子之大小亦并非限速因素。
TAT已表明不仅可增强细胞内传递,而且可增强细胞核传递,且因此已研究用于核酸传递。据显示,结合至反义寡核苷酸之TAT肽将寡核苷酸传递至细胞核。亦已发现, TAT肽在内化之后与BODIPY-脑酰胺一起共定位在高基体内部,BODIPY-脑酰胺为高基体之标记。因此,极有可能存在自早期内体至高基体之直接移行,而未进入晚期内体。可能存在分泌路径,其中肽自内质网进入胞溶质。基因疗法已在遗传性、后天性及神经退化性病症之治疗方面展现出潜在的意义。在非病毒基因传递方法中,正在研究各种药物传递系统及聚合物,诸如脂质体、阳离子脂质-DNA、聚合物复合物。为解决非病毒基因表现载体之相对较低效的细胞吸收,已探索出将TAT肽与载体结合。
Kleeman等人已证明,在气管内投药之后,在聚乙烯亚胺(PEI)经由聚乙二醇(PEG)间隔剂共价偶合至TAT之情况下,肺泡基底上皮细胞中之基因表现展现出之小鼠肺部的活体内转染效率高于未结合的PEG复合物。在Rudolph等人之类似研究中,与二聚HIV-1 TAT结合之固体脂质粒子展现出对肺部之基因传递增强。
CPP通常具有胺基酸组合物,该胺基酸组合物含有高相对丰度之带正电荷的胺基酸,诸如离胺酸或精胺酸,或其序列含有交替模式之极性/带电胺基酸及非极性疏水性胺基酸。这两种类型之结构分别称为聚阳离子结构或两性结构。第三类CPP包含疏水性肽,仅含有非极性残基,具有对细胞吸收至关重要的低净电荷或疏水性胺基酸基团。在细胞穿透肽中,富含精胺酸之细胞穿透肽之研究最为广泛。实例包括来自HIV转活化剂蛋白 TAT之TAT肽、穿膜肽、来自果蝇之触角足突变蛋白之结构域(该结构域具有16个胺基酸)、禽兽棚病毒(FHV)外壳肽(序列35-49)及寡聚精胺酸。
生物可降解奈米粒子介导之细胞内传递为动态过程;涉及内饮作用、胞外分泌及分选至不同细胞内区室中。由此看来,NP表面及其与细胞表面之相互作用控制着生物可降解奈米粒子之吸收及细胞内移行,且因此控制着所囊封之治疗剂之吸收及细胞内移行。
病毒载体为分子生物学家常用于将遗传物质传递至细胞中之工具。此过程可以在活有机体内部(活体内)或在细胞培养物中(活体外)进行。因此,病毒载体为用于穿透细胞之药物传递系统之适用选项。
细胞穿透肽及生物可降解奈米粒子不仅可以用于修饰药物,而且可以与载剂结合以增强跨膜效应。
双嘧达莫为平衡型核苷转运体(ENT)抑制剂。核苷转运体(NT)在跨越细胞膜转运核苷时起重要作用。双嘧达莫阻断平衡型核苷转运体(ENT),其有助于腺苷之跨膜扩散。双嘧达莫将增加细胞外内源性腺苷浓度,主要在腺苷之细胞外形成增加之情况下,诸如发生在缺氧或炎症期间。然而,由双嘧达莫诱导之细胞外内源性腺苷浓度引起血管扩张,血管扩张有助于器官灌注之代谢控制。双嘧达莫负荷心肌成像为一种用于诊断且评估冠状动脉疾病之成功且广泛使用的技术。因静脉内双嘧达莫引起之冠状血管扩张与通向依赖侧支之心肌的血流量显著降低相关,与CAD患者体内的冠状窃流一致。另外,进一步研究发现双嘧达莫在诸多器官中之血管收缩剂及血管扩张剂效应,该等器官包括肾脏、肺、胰脏、大脑等。
在一些器官中,双嘧达莫不仅造成血管收缩,亦可以导致低血压及后续副作用,诸如由于心脏血管扩张所致之眩晕及心悸。降血压作用使双嘧达莫不适合治疗生理学上不稳定之患者,诸如患有(但不限于)败血症、缺血性卒中、出血性卒中、急性肺损伤、急性肝脏损伤、心肌梗塞及心肾症候群之彼等患者。此外,双嘧达莫之血流量限制作用使其在涉及血管丰富之器官的疾病治疗方面的应用受到限制。
因为双嘧达莫之药理学作用主要系针对细胞膜,所以针对膜穿透所设计之传递系统避免与膜上之平衡型核苷转运体结合同时增强细胞内信号转导及PPARγ调控,可以防止由于心血管扩张增加及局部血流量限制所致之组织灌注不足的影响。由于血压降低,双嘧达莫在急性及重症患者方面之临床应用的限制性因此会上升。
双嘧达莫亦为非选择性磷酸二酯酶抑制剂。增加细胞内药物传递将增强双嘧达莫对细胞内PDE之抑制。PDE家族之成员具有独特的细胞及组织特异性分布。视PDE在不同组织中之细胞膜上或在细胞质中之分布概况而定,双嘧达莫可以用作消炎剂、抗氧化剂、抗纤维剂化药剂及平滑肌松弛剂来治疗与PDE调控相关之疾病。
PDE之独特的细胞及组织特异性分布显示于下表中(参见US 2012/0065165):
双嘧达莫穿透膜之能力增加可以有助于抑制特定组织中之PDE3、PDE5及PDE8且赋予双嘧达莫在与PDE3、PDE5及PDE8相关之疾病方面的治疗功效。在此情况下,双嘧达莫可以如同其他PDE5抑制剂一样,用于治疗下泌尿道功能障碍及勃起功能障碍。此外,因为双嘧达莫为非选择性PDE抑制剂,所以其可以用于在藉由跨膜药物传递系统传递时治疗PDE相关疾病。
在一实施例中,本发明之式(I)化合物囊封于穿透细胞之药物传递系统中以便传递至细胞中。在一较佳实施例中,穿透细胞之药物传递系统为囊泡、聚合物囊泡、奈米粒子、脂质体、奈米悬浮粒子、固体脂质奈米粒子、磁性奈米载剂、微胞、大分子结合物或微粒药物载剂。较佳地,穿透细胞之药物传递系统为脂质体。适合于本发明之脂质体之直径在约100-300nm、较佳约150-280nm、更佳约180-270nm之范围内。
在本发明之另一实施例中,穿透细胞之药物传递系统可以为囊泡、聚合物囊泡或直径小于1μm之聚合物。可以基于表面电势、亲水性/疏水性、大小、形态、形状及/或表面曲率进行修改。
本发明之脂质体调配物可以包含具有各种性质(例如,单层或多层)、组成、大小及特征;囊封于具有不同组成、pH及渗透强度之水性介质中之小泡。在一较佳实施例中,脂质体脂质层膜之主要组分选自由天然或合成磷脂组成之群,该等天然或合成磷脂诸如以下所列的彼等磷脂:
-1,2-二月桂酰基-sn-甘油-3-磷酸胆碱(DLPC)
-1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱(DMPC)
-1,2-二软脂酰基-sn-甘油-3-磷酸胆碱(DPPC)
-1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)
-1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)
-1,2-二肉豆蔻酰基-sn-甘油-3-磷酸乙醇胺(DMPE)
-1,2-二软脂酰基-sn-甘油-3-磷酸乙醇胺(DPPE)
-1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺(DSPE)
-1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)
-1-肉豆蔻酰基-2-软脂酰基-sn-甘油-3-磷酸胆碱(MPPC)
-1-软脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱(PMPC)
-1-硬脂酰基-2-软脂酰基-sn-甘油-3-磷酸胆碱(SPPC)
-1-软脂酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱(PSPC)
-1,2-二肉豆蔻酰基-sn-甘油-3-[磷酸-外消旋-(1-甘油)](DMPG)
-1,2-二软脂酰基-sn-甘油-3-[磷酸-外消旋-(1-甘油)](DPPG)
-1,2-二硬脂酰基-sn-甘油-3-[磷酸-外消旋-(1-甘油)](DSPG)
-1,2-二油酰基-sn-甘油-3-[磷酸-外消旋-(1-甘油)](DOPG)
-1,2-二肉豆蔻酰基-sn-甘油-3-磷酸(DMPA)
-1,2-二软脂酰基-sn-甘油-3-磷酸(DPPA)
-1,2-二软脂酰基-sn-甘油-3-[磷酸-L-丝胺酸](DPPS)
-磷脂酰丝胺酸(PS),及
-天然L-a-磷脂酰胆碱(来自鸡蛋、EPC,或来自大豆、SPC及HSPC)。
较佳磷脂为长饱和磷脂,例如烷基链超过12个、较佳超过14个、更佳超过16个、最佳超过18个碳原子之彼等磷脂。
根据本发明使用之较佳脂质体组合物较佳为脂质体为单层及/或多层脂质体之彼等脂质体组合物,且包含:
(i)1莫耳%至100莫耳%、较佳40莫耳%至70莫耳%生理学上可接受之磷脂,该等磷脂较佳选自由以下组成之群:DLPC、DMPC、DPPC、DSPC、DOPC、DMPE、DPPE、DSPE、DOPE、MPPC、PMPC、SPPC、PSPC、DMPG、DPPG、DSPG、DOPG、DMPA、 DPPA、DPPS、PS,EPC、SPC及HSPC;
(ii)1莫耳%至100莫耳%、较佳40莫耳%至70莫耳%鞘脂,较佳鞘磷脂;
(iii)1莫耳%至100莫耳%、较佳40莫耳%至70莫耳%界面活性剂,较佳以疏水性烷基醚(例如,Brij)、烷基酯、聚山梨醇酯、脱水山梨糖醇酯及/或烷基酰胺为特征之界面活性剂;
(iv)5莫耳%至100莫耳%、较佳50莫耳%至100莫耳%两亲媒性聚合物及/或共聚物,较佳嵌段共聚物,该等嵌段共聚物包含至少一个亲水性聚合物或共聚物嵌段,诸如聚乙二醇;及至少一个疏水性聚合物或共聚物嵌段,诸如聚(丙交酯)、聚(己内酯)、聚(氧化丁烯)、聚(氧化苯乙烯)、聚(苯乙烯)、聚(乙基乙烯)或聚二甲基硅氧烷;
(v)0至60莫耳%、较佳20莫耳%至50莫耳%毒素滞留增强型化合物,较佳固醇衍生物,较佳胆固醇,或
(vi)0至30莫耳%、较佳1莫耳%至5莫耳%位阻稳定剂,较佳聚乙二醇化化合物,较佳聚乙二醇化脂质,更佳DSPE-PEG。
在一较佳实施例中,类似脂质体之小泡由聚合物制成且不含脂质,出于此原因,其形式上不视为脂质体,而是称作聚合物囊泡。然而,出于本发明之目的,聚合物囊泡意欲由术语脂质体所涵盖,该术语用于限定本发明及申请专利范围。
类似地,由合成界面活性剂制成且不含脂质的类似脂质体之小泡称作囊泡。然而,出于本发明之目的,囊泡意欲由术语脂质体涵盖,该术语用于限定本发明及申请专利范围。
在本发明之一实施例中,可以使用不同高分子聚合物之聚合,该等高分子聚合物包含呈三嵌段共聚物形式之聚合物,诸如ABA及BAB;及呈嵌段共聚物形式之聚合物,诸如PLLA-PEG、PLGA-PEG、PLA-PEG、PLLA-mPEG、PLGA-mPEG及PLA-mPEG。可以设计各种形状,诸如星状及L形,包括PEG-(PLGA)8、PEG-(PLLA)8及PEG-(PDLA)8 星型嵌段共聚物。可以使用聚乙二醇化改质对诸如聚合物媒剂及脂质体之任何媒剂进行改质,从而达成降低血浆蛋白质之结合速率的效果(参见Park,J.等人,(2009)「PEGylated PLGA nanoparticles for theimproved delivery of doxorubicin.Nanomedicine.」 5(4):410-418;Lück,M.等人,(1998)「Plasma protein adsorption on biodegradable microspheres consisting ofpoly(D,L-lactide-co-glycolide),poly(L-lactide)or ABA triblock copolymerscontaining poly(oxyethylene).Influence of production method and polymercomposition.」J.Control Release.55(2-3):107-20;及Sempf,K.等人,(2013)「Adsorption of plasma proteins on uncoated PLGA nanoparticles.」Eur.J.Pharm.Biopharm. 85(1):53-60)。
不应该藉由基于体重之简单转换,自动物剂量外推至人类等效剂量(HED)。食品与药物管理局已提出,动物剂量至人类剂量之外推仅经由针对BSA进行标准化来正确地进行,常常用mg/m2表示。人类等效剂量可以更恰当地使用下式计算:HED(mg/kg)=动物剂量(mg/kg)乘以动物Km/人类Km。为将小鼠中所用之剂量转换成基于人类表面积之剂量,22.4mg/kg(鲍氏小鼠剂量(Baur's mouse dose))乘以小鼠Km因子(3)且随后除以人类Km因子(37)(参见下表)。
基于来自FDA草案准则之数据的值
为将以mg/kg表示之剂量转换成以mg/m2计之剂量,乘以Km值。根据本发明,脂质体-双嘧达莫之有效剂量在小鼠中为10mg/kg-100mg/kg,在仓鼠中为6-60mg/kg,在大鼠中为5-50mg/kg,在天竺鼠中为3.75-37.5mg/kg,在兔子中为2.5-25mg/kg,在猴子中为2.5-25mg/kg,在狗中为1.5-15mg/kg,在猫中为2.4-24mg/kg,在狒狒中为1.5-15 mg/kg,在儿童中为1.2-12mg/kg,且在成人中为0.81-8.1mg/kg。考虑到各物种之间的药物敏感性差异,在不限制物种之情况下,最宽剂量范围为0.4-160mg/kg,较佳0.6-120 mg/kg,更佳0.8mg/kg-100mg/kg。
现已大体上描述了本发明,本发明可以参考以下实例更容易了解,该等实例提供用于制造本发明之医药组合物的例示性方案及其在增强急性卒中之治疗方面的用途。该等实例仅出于说明之目的提供,且不希望以任何方式限制本发明之范畴。已尽力确保关于所用数字(例如量、温度等)之准确性,但当然应该允许一些实验误差及偏差。
实例
实例1:制备双嘧达莫脂质体
用带正电荷及中性电荷之磷脂及胆固醇制备脂质体,其中胆固醇之莫耳百分比为5%至75%,存在或不存在PEG2000-DSPE,磷脂为5莫耳%。制备单层小微脂粒。经干燥之脂质膜用硫酸铵水合且经由一系列聚碳酸酯膜过滤器依序挤出。经由跨膜pH梯度或脱水-复水,将双嘧达莫囊封至脂质体中,且挤制脂质体之直径在100-350nm之范围内。脂质体-双嘧达莫之直径为约169至276nm,如图5中所示。
实例2:经双嘧达莫脂质体处理之HEK293细胞
实例2.1:PPARγ在经双嘧达莫脂质体处理之细胞中之表现
该分析中所用之细胞株为人胎肾细胞HEK293。该等细胞用下表1中所示之试剂处理。
表1:实验设计
在处理之后0h、3h及12h,收集细胞。所收集之细胞用150μL缓冲液A(10mM HepespH=7.9、1.5mM MgCl2、10mM KCl、1.0mM DTT、0.1%Triton-X 100)洗涤,且在3000g下在4℃下离心10分钟。收集含有胞溶质蛋白质之上清液,且集结粒用50μL 缓冲液B(20mM HepespH=7.9、1.5mM MgCl2、0.42M NaCl、1.0mM DTT、1.0M PMSF、 0.2mM EDTA)再悬浮,且在冰上培育30分钟,随后在12000g下在4℃下离心10分钟。随后收集含有核蛋白质之上清液,且使用西方墨点法分析P65蛋白质之表现,其说明 PPARγ之活化。方法如下:
使用布莱德福分析(Bradford assay)量测蛋白质浓度。将6×样品缓冲液(0.8mMTris-HCl、10mM EDTA、10%SDS、60%甘油、0.6Mβ-巯基乙醇、0.06%溴酚蓝,pH 6.8) 添加至50μg细胞核蛋白质中且将相等体积之溶解缓冲液添加至样品中。在95℃下加热 10分钟以使蛋白质变性之后,立即在冰上冷却样品。
样品随后藉由10%SDS-PAGE电泳(100V)分离且藉由湿式墨点法自SDS-PAGE凝胶转移至PVDF膜。PVDF膜随后在室温下经5%脱脂乳处理60分钟以阻断非特异性结合。该等膜与初级抗体一起在4℃下培育隔夜且用PBST洗涤三次。该等膜与二级抗体一起在室温下培育60分钟且用PBST洗涤三次。该等膜随后再用PBS洗涤一次且与增强型化学发光(ECL)受质一起培育以便侦测。使用自动化化学发光及荧光成像系统(UVP Biospectrum)获得影像之像片。测试组相对于对照组之PPARγ表现显示于图7a(12小时) 及图7b(0及3小时)中。
在此实验中所用之初级抗体为MILLIPORE之兔抗人类PPARγ抗体(1:1000)(目录号:07-466)及GeneTex之兔抗人类核纤层蛋白A/C(1:1000)(目录号:GTX62457)。在此实验中所用之二级抗体为sigma之小鼠抗兔HRP(1:3000)(ab6721)。
实例2.2:经双嘧达莫脂质体处理之细胞之活力
使用细胞计数套组-8(Dojindo Laboratories,Japan),遵循制造商之说明书,评估在初始处理后24小时活细胞之数目,且使用培养盘读取器Multiskan EX(Thermo FisherScientific Inc.,Waltham,MA)量测各孔上清液在450nm波长下之吸亮度。数据显示于图 8中。
实例3:患有LPS诱发之败血症之小鼠的存活率分析
在此研究中使用8-12周龄之雄性C57Bl/6J小鼠。将其饲养在经空气调节之环境中且在6am至18pm光循环下,且随意饲喂标准啮齿动物食物。每次施加时,LPS(大肠杆菌(Escherichia coli)0111:B4)(SigmaAldrich,Milwaukee,WI,USA)均新溶解于无生脓原之无菌水中。首先,给小鼠腹膜内注射LPS(16mg/kg),且过72小时观测存活率。藉由初步实验确定LPS之剂量,该剂量显示,在经注射之动物中,一半动物之存活时间久于24小时。在LPS处理之后1小时投与双嘧达莫。
实例4:侦测血浆中之生物标记
4.1:肝脏标记(AST、ALT)及肾脏标记(BUN、肌酸酐)
在实验之前及在进入实验24小时时,自各动物收集血液样品进行生物化学量测。藉由离心分离样品,且将血清储存在-80℃下直至分析。使用Merck分析套组(Darmstadt,Germany)量测血清总胆固醇。亦使用SPOTCHEMTM自动干式化学系统(SP-4410;Arkray,Shanghai,Japan)量测血清血脲氮(BUN)、肌酸酐、丙胺酸转胺酶(ALT)及天冬胺酸转胺酶(AST)。数据显示于图9中。
图9显示,LPS处理诱发肝脏及肾脏损伤,肝脏及肾脏损伤使得血液中之天冬胺酸转胺酶(AST)、丙胺酸转胺酶(ALT)、肌酸酐及BUN含量显著增加。用低剂量之双嘧达莫或脂质体双嘧达莫处理可缓解LPS诱导的血清中之AST、ALT、肌酸酐及BUN含量的增加情况。这一点说明,双嘧达莫具有治疗急性或慢性肝脏及肾脏炎症以及败血症之治疗功效。另外,因为高剂量之双嘧达莫导致血压改变且影响生理条件及存活率,所以脂质体双嘧达莫之剂量依赖性功效可以隐含较宽范围之适用剂量。
实例5:量测组织损伤
5.1:IHC
自肝脏及肺制备石蜡包埋切片(3μm),将其固定于经10%磷酸盐缓冲之福尔马林(formalin)中。使用过碘酸-希夫(Periodic acid-Schiff;PAS)染色,由不知情之观察者用光学显微镜(Nikon E800;Melville,NY)分析形态。关于各小鼠,检查至少10个高倍视野。肝脏及肺组织之HE染色分别显示于图10及图11中。
在LPS处理之后72小时,在经HE染色之肝脏及肺切片中观察到由经累积之巨噬细胞及嗜中性白血球诱发的过度炎症及组织损伤。用双嘧达莫或脂质体双嘧达莫后处理可减弱组织损伤及炎症。相比于游离形式之双嘧达莫,在组织学上,脂质体双嘧达莫展现较佳的治疗功效。
5.2:PPARγ在肾脏及肝脏中之活化状态
使小鼠组织在10mM Tris-HCl(pH 7.5)、1mM EDTA、250mM蔗糖、10mM 2-巯基乙醇(Nacarai tesque,Inc.)、蛋白酶抑制剂(cOmplete,Mini,Roche Diagnostics)及磷酸酶抑制剂(PhosSTOP,Roche Diagnostics)中均质化。在1000rpm下运作之Braun Potter S均质机中使用六个上下冲程(up-and-down stroke)。对匀浆进行离心(800g),且弃去集结粒。再次在12,000g下使上清液离心10min,且收集所得上清液。在收集样品之后,藉由布莱德福分析量测蛋白质浓度。将6×样品缓冲液(0.8mM Tris-HCl、10mM EDTA、10% SDS、60%甘油、0.6Mβ-巯基乙醇、0.06%溴酚蓝,pH 6.8)添加至50μg全细胞蛋白质中且将相等体积之溶解缓冲液添加至样品中。在95℃下加热10分钟以使蛋白质变性之后,立即在冰上冷却样品。
样品随后藉由10%SDS-PAGE电泳(100V)分离且藉由湿式墨点法自SDS-PAGE凝胶转移至PVDF膜。PVDF膜随后在室温下经5%脱脂乳处理60分钟以阻断非特异性结合。该等膜与初级抗体一起在4℃下培育隔夜且用PBST洗涤三次。该等膜与二级抗体(抗兔IgG,sigma)一起在室温下培育60分钟且用PBST洗涤三次。该等膜随后再用PBS洗涤一次且与增强型化学发光(ECL)受质一起培育以便侦测。使用自动化化学发光及荧光成像系统(UVPBiospectrum)获得影像之像片。
所用抗体:t-PPARγ(1:1000;abcam ab191407)及β-肌动蛋白(1:1000;GeneTexGTX109639)。肾脏及肝脏中之t-PPARγ表现之数据分别显示于图12a及图12b中。
根据实验结果,显然可知,无论在肾脏组织中抑或在肝脏组织中,双嘧达莫或脂质体双嘧达莫均具有以剂量依赖性方式诱导PPARγ表现之活性。由于藉由脂质体经由吞噬作用及融合,药物至细胞中之穿透增强,所以PPARγ之表现大大增加。
实例6:双嘧达莫脂质体对血压之影响
双嘧达莫具有降血压作用。在各种急性及重大病况之治疗中,降低血压可以影响疾病之预后。因此,侦测本发明之双嘧达莫脂质体对血压之影响可以允许评估临床使用可行的最大剂量。
在静脉内投与以下药剂之后,使用非侵袭性血压装置量测小鼠之血压:(1)生理盐水; (2)LPS;(3)LPS,随后双嘧达莫(游离形式),10mg/kg;(4)LPS,随后双嘧达莫(游离形式),100mg/kg;(5)LPS,随后双嘧达莫脂质体,10mg/kg;及(6)LPS,随后双嘧达莫脂质体,100mg/kg。结果显示于图13a中。
不同剂量(在药物治疗之前无LPS)之额外测试结果显示于图13b中。
以上实验数据证明,藉由提高双嘧达莫进入细胞之能力,双嘧达莫之药理学机制将改变,引起双嘧达莫对PPARγ表现之活性增加且双嘧达莫在细胞膜上之活性降低,从而减少药物对血管之刺激且减少随之而来的对血流量的严重干扰。藉由提高双嘧达莫对PPARγ表现之活性,双嘧达莫展现出治疗多种疾病之潜能。藉由多种机制之作用,双嘧达莫经由PPARγ路径之消炎及抗凋亡活性得以增加。双嘧达莫可以用于治疗急性及重症疾病及小型哺乳动物,且不干扰血压。
Claims (23)
2.根据权利要求1所述的用途,其中所述二(羟(C1-C6)烷基)胺基为N,N-二(羟乙基)胺基。
3.根据权利要求1所述的用途,其中所述化合物为双嘧达莫。
4.根据权利要求1至3中任一权利要求所述的用途,其中所述化合物囊封于穿透细胞之药物传递系统中。
5.根据权利要求4所述的用途,其中所述穿透细胞之药物传递系统为脂质体。
6.根据权利要求5所述的用途,其中所述脂质体之直径在约100-300nm之范围内。
7.根据权利要求1所述的用途,其中所述个体为人类或非人类哺乳动物。
8.根据权利要求7所述的用途,其中所述非人类哺乳动物为猫或狗。
9.根据权利要求1至3中任一权利要求所述的用途,其中所述增强个体中PPARγ之表现和核转位可用于预防或治疗系选自由以下各者组成之群的病症或病况:肝损伤、肾损伤、肺损伤、肝肾损伤、肾肺损伤、和肝肾肺多器官损伤。
10.根据权利要求9所述的用途,其中所述肝损伤系通过降低血清中丙胺酸转胺酶(ALT)、和/或天冬胺酸转胺酶(AST)的含量来预防或治疗。
11.根据权利要求9所述的用途,其中所述肾损伤系通过降低血清中血脲氮(BUN)、和/或肌酸酐的含量来预防或治疗。
12.根据权利要求9所述的用途,其中所述肺损伤系通过降低巨噬细胞及嗜中性白血球的诱发来预防或治疗。
13.一种医药组合物的用途,其系用于增强个体中PPARγ之表现和核转位以减少由药物与细胞膜受体相互作用导致之血管扩张副作用的药剂,其中所述药剂包含基于穿透细胞之药物传递系统,其中所述医药组合物包含治疗有效量之如权利要求1至3中任一权利要求中所定义之式(I)化合物或其医药学上可接受之盐。
14.根据权利要求13所述的用途,其中所述穿透细胞之药物传递系统为脂质体。
15.根据权利要求14所述的用途,其中所述脂质体之直径在约100-300nm之范围内。
16.根据权利要求14所述的用途,其中所述脂质体带正电荷或带有中性电荷。
17.根据权利要求14所述的用途,其中所述剂量在0.4-160mg/kg之范围内。
18.根据权利要求14所述的用途,其中所述个体为人类或非人类哺乳动物。
19.根据权利要求18所述的用途,其中所述非人类哺乳动物为猫或狗。
20.根据权利要求13至19中任一权利要求所述的用途,其中所述增强个体中PPARγ之表现和核转位可用于预防或治疗系选自由以下各者组成之群的病症或病况:肝损伤、肾损伤、肺损伤、肝肾损伤、肾肺损伤、和肝肾肺多器官损伤。
21.根据权利要求20所述的用途,其中所述肝损伤系通过降低血清中丙胺酸转胺酶(ALT)、和/或天冬胺酸转胺酶(AST)的含量来预防或治疗。
22.根据权利要求20所述的用途,其中所述肾损伤系通过降低血清中血脲氮(BUN)、和/或肌酸酐的含量来预防或治疗。
23.根据权利要求20所述的用途,其中所述肺损伤系通过降低巨噬细胞及嗜中性白血球的诱发来预防或治疗。
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