CN105228619B - 治疗c型肝炎病毒感染的医药组合物 - Google Patents
治疗c型肝炎病毒感染的医药组合物 Download PDFInfo
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Abstract
本发明涉及一种治疗C型肝炎病毒的医药组合物,包括(a)有效剂量的至少一HCV抑制剂,其选自由HCV NS3抑制剂、HCV NS5B抑制剂、雷巴威林、以及干扰素‑α(IFN‑α)所组成的组;以及(b)有效剂量的如式(I)所示的抗HCV化合物。
Description
背景技术
C型肝炎病毒(HCV)是一种小型包膜RNA病毒,影响全球近170万人口,为 C型肝炎及肝病的主要病因。HCV感染导致慢性肝病、肝硬化及相关并发症,包括肝功能衰竭、肝门脉高压及肝癌发生。
慢性HCV治疗的主要目标在于消灭病毒并防止潜在威胁生命的并发症发生。慢性HCV治疗的主流是聚乙二醇化的IFN-α(PEGylated IFN-α)及雷巴威林 (ribavirin)。然而,上述化合物的耐受性差,且可能最终产生不理想的缓解率及高不良反应发生率,包括类流感症状、抑郁症及贫血。对于全世界人口的主要基因型的基因型1的感染,其持续病毒清除率仅40-50%。
因此,对于C型肝炎的研究发展而言,提升特异性抗病毒治疗的效果及更佳的耐受性是一项重大的公共卫生目标。
发明概述
本发明意外发现当某些抗HCV化合物(譬如DBPR110及DBPR111)与一种或以上的HCV抑制剂(譬如特拉普韦(telaprevir)、波西普韦(boceprevir)、索非布韦(sofosbuvir)、雷巴威林及干扰素-α)结合使用时,对于抑制HCV能产生协同效应(synergistic effect)。
因此,本发明涉及一种治疗C型肝炎病毒的方法。该方法包括向有需要的主体给予(a)有效剂量的至少一HCV抑制剂,其选自由HCV NS3抑制剂、HCV NS5B抑制剂、雷巴威林(ribavirin)以及干扰素-α(IFN-α)所组成的组;以及(b)有效剂量的如下文所述的抗HCV化合物。举例来说,该抗HCV化合物是DBPR110或 DBPR111。
本发明的细节及实施例将于下文中详加描述。由文中描述及权利要求书可显而易见地了解本发明其它特征、目的及优点。
发明详细说明
本发明是一种治疗HCV感染的方法。该方法包括向有需要的主体给予(a)有效剂量的至少一HCV抑制剂,其选自由HCV NS3抑制剂、HCV NS5B抑制剂、雷巴威林(ribavirin)以及干扰素-α(IFN-α)所组成的组;以及(b)有效剂量的抗HCV化合物,其如式(I)所示:
在式(I)中,A是B是每一C及D各自独立为亚芳基或亚杂芳基;每一R1、R2、R3、R4、R5及R6各自独立为烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、卤素、杂环烯基、氰基或硝基;每一R7及R8各自独立为氢、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;每一R9和R10各自独立为氢或烷基;每一R11及R12各自独立为氢、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;每一X1及X2各自独立为C(O)或C(S);每一Y1和Y2各自独立为:被删除的、SO、SO2、C(O)、C(O)O、C(O)NRa、C(S)NRa或SO2NRa,其中Ra是氢、烷基、环烷基、杂环烷基、芳基或杂芳基;每一m及n各自独立为0、1、2、3或 4;每一p及q各自独立为0或1;每一r及t各自独立为1、2或3;且每一u及 v各自独立为0、1、2、3、4、5、6、7或8。
举例来说,该抗HCV化合物如下式(II)所示:
于其它实施例中,该抗HCV化合物如下式(III)所示:
上述抗HCV化合物可包括一种或以上的下述特征。A及B分别为C及D分别为亚苯基。X1及X2分别为C(O)。Y1及Y2各自独立为 SO2、C(O)或C(O)O。R7及R8分别为苯基。R11及R12分别各自独立为C1-5烷基或 C3-5环烷基。t及r分别为2。A与B不同。p、m、n、q、u及v分别为0。p、 m、n及q分别为0,u及v分别为1,且R5及R6分别为F。
上述抗HCV化合物描述于美国专利申请号12/958,734(公开号为US2011/0136799)。
「烷基」一词是指直链或支链的单价烃基,其包含1-20个碳原子(如:C1- C10),烷基举例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基及第三丁基。「烯基」一词是指直链或支链的单价或二价碳氢基团,其包含 2-20个碳原子(如:C2-C10)及一个以上的双键,烯基举例包括但不限于:乙烯基、丙烯基及烯丙基(allyl)。「炔基」一词是指直链或支链的单价烃基,其包含 2-20个碳原子(如:C2-C10)及一个以上的参键。炔基举例包括但不限于:乙炔基、1-丙炔基、1-及2-丁炔基及1-甲基-2-丁炔基。
「环烷基」一词是指单价或二价饱和碳氢环结构,其具有3至30个碳原子 (如:C3-C12)。环烷基举例包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基及环辛基。「环烯基」一词是指单价或二价非芳香性碳氢环结构,其具有3至30个碳原子(如:C3-C12)及一个以上的双键。举例包括:环戊烯基、环己烯基及环庚烯基。「杂环烷基」一词是指单价或二价非芳香性5-8元单环结构、8-12元双环结构或11-14元三环结构,其具有一个以上的杂原子(如O、 N、S或Se),杂环烷基举例包括但不限于:哌嗪基(piperazinyl)、吡咯烷基(pyrrolidinyl)、二恶烷基(dioxanyl)、吗啉基(morpholinyl)及四氢呋喃基(tetrahydrofuranyl)。「杂环烯基」一词是指单价或二价非芳香性5-8元单环结构、 8-12元双环结构或11-14元三环结构,其具有一个以上的杂原子(如O、N、S或 Se)及一个以上的双键。
「芳基」一词是指单价6碳单环状、10碳双环状、14碳三环状芳香环结构,芳基举例包括但不限于:苯基、萘基及蒽基。「亚芳基」一词是指二价6碳单环状(譬如亚苯基)、10碳双环状(譬如亚萘基)、14碳三环状芳香环结构。「杂芳基」一词是指单价芳香性5-8元单环、8-12元双环或11-14元三环结构,其具有一个以上的杂原子(如O、N、S或Se),杂芳基举例包括但不限于:吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯并咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、噻吩基(thienyl)、喹啉基(quinolinyl)、吲哚基 (indolyl)及噻唑基(thiazolyl)。「亚杂芳基」一词是指二价芳香性5-8元单环、8-12 元双环或11-14元三环结构,其具有一个以上的杂原子(如O、N、S或Se)。
上述的烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、芳基、亚芳基、杂芳基及亚杂芳基,包括经取代及未经取代的两种基团。在环烷基、杂环烷基、环烯基、杂环烯基、芳基及杂芳基上的可能的取代基,举例包括但不限于:C1-C10烷基(如三氟甲基)、C2-C10烯基、C2-C16炔基(如芳基炔基)、C3- C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基(如卤代芳基或经卤素取代的芳基)、芳氧基、杂芳基、杂芳氧基、氨基、 C1-C10烷氨基、芳氨基、羟基、卤素、氧代(O=)、硫代(S=)、硫基(thio)、硅烷基(silyl)、C1-C10烷硫基、芳硫基、C1-C10烷磺酰基(alkylsulfonyl)、芳磺酰基(arylsulfonyl)、酰基胺(acylamino)、氨基酰(aminoacyl)、氨基硫酰(aminothioacyl)、脒基(amidino)、硫醇基(mercapto)、酰氨基(amido)、硫脲基(thioureido)、硫氰酸基(thiocyanato)、磺酰氨基(sulfonamido)、胍基(guanidine)、脲基(ureido)、氰基、硝基、酰基、硫酰基、酰氧基(acyloxy)、脲基(carbamido)、氨甲酰基(carbamyl)、羧基(carboxyl)及羧酸酯基。另一方面,在烷基、烯基或炔基上的可能取代基,包括 C1-C10烷基之外的所有上述取代基。环烷基、环烯基、杂环烷基、杂环烯基、芳基及杂芳基亦可互相稠合。
如果可以实施的话,上述稠合多环化合物不仅包括化合物本身,也包括其盐类、其溶剂化物以及其前驱药。举例而言,多环化合物上带有正电的基团(例如氨基)可与阴离子形成盐类,而适合的阴离子包含氯离子、溴离子、碘离子、硫酸根、硫酸氢根、磺胺酸根、硝酸根、磷酸根、柠檬酸根、甲磺酸根、三氟乙酸根、谷氨酸根、醛糖酸根、戊二酸根、苹果酸根、马来酸根、琥珀酸根、富马酸根、酒石酸根、甲苯磺酸根、水杨酸根、乳酸根、萘磺酸根及乙酸根。同样,多环化合物上带有负电的基团(例如羧酸根)可与阳离子形成盐类,而适合的阳离子包含钠离子、钾离子、镁离子、钙离子及铵离子(如四甲基铵离子)。该多环化合物亦包含那些含有四级氮原子的盐类。前驱药形式举例包含:酯类及其它医药上可接受的衍生物,根据向主体的给药方式,其能够提供活性多环化合物。
较佳为,于本治疗方法中所使用的抗HCV化合物为DBPR110,其具有以下结构:
另一较佳抗HCV化合物为DBPR111,其具有以下结构:
上述抗HCV化合物可利用一般常规方法或于美国专利申请号12/958,734所公开的方法合成。
除了上述的抗HCV化合物,亦可将一种或以上(如:两种)的其它HCV 抑制剂,即HCVNS3抑制剂、HCV NS5B抑制剂、雷巴威林(ribavirin)或干扰素- α(IFN-α),给予主体。举例来说,合并两种抑制剂可包括(i)抗HCV抑制剂和IFN- α;以及(ii)抗HCV抑制剂和HCV NS3抑制剂。合并三种抑制剂可包括(i)抗HCV 抑制剂、IFN-α和HCV NS3抑制剂;(ii)抗HCV化合物、-HCV NS3抑制剂和 HCV NS5B抑制剂;以及(iii)抗HCV化合物和两不同的NS5B抑制剂。各种HCV 抑制剂为本领域公知。参考譬如:Kwo与Zhao,Clin Liver Dis 15:537-53(2011);Kwong et al.,Curr Opin Pharmacol 8:522-31(2008);Legrand-Abravanel et al.,Expert Opin Investig Drugs 19:963-75(2010);Liapakis与Jacobson,Clin Liver Dis15:555-71(2011); Lemm et al.,J Virol 84:482-91(2010);Naggie et al.,JAntimicrob Chemother 65:2063-9 (2010);WO2012/009394;WO2012/018829;以及WO2011/046811。
举例来说,该HCV NS3抑制剂可为波西普韦(boceprevir)或特拉普韦(telaprevir) (即VX950)。HCV NS5B抑制剂的例子为索非布韦(sofosbuvir)(Pharmasset,Inc., NJ)。雷巴威林(ribavirin)可经由多种机制抑制HCV。且如同现有技术所记载, IFN-α亦为抗HCV药剂,可未经修饰或经聚乙二醇化。该些HCV抑制剂可通过标准制法制备或由市售购得。
为了实现本发明的治疗方法,上述抗HCV化合物及HCV抑制剂可以共同形成单一组合物给予患者、于同一时间或不同时间分别给予患者。举例来说,可将一医药组合物给予患者,该医药组合物包括有效剂量的抗HCV化合物、有效剂量的HCV抑制剂以及医药上可接受性的载体。或者,包括抗HCV化合物的医药组合物及包括其它HCV抑制剂的医药组合物可分别给予患者。
于此所使用的「治疗」一词,是指将化合物给予受HCV感染或具有此病症的症状或朝此病症发展的倾向的主体,以期达到治疗、治愈、减轻、缓和、改变、补救、改良、改善或影响上述病症、此病症的症状或朝此病症发展。术语「有效剂量」是指活性药剂的量,当与一种或以上其它活性药剂组合使用时,能够对于治疗主体产生预期疗效所需的剂量。
上述抗HCV化合物及HCV抑制剂可透过口服、非口服、喷雾吸入、局部、经直肠、经鼻、舌下、阴道或经由植入型药盒(implanted reservoir)等方式给药。于此使用的「非口服」(parenteral)是指皮下注射、皮内注射、静脉内注射、肌肉内注射、关节腔内注射、动脉内注射、关节液内注射、胸腔内注射、脊髓内注射、疾病部位内注射及颅内注射或注入技术。
无菌可注射的组合物,例如无菌可注射水性或油性悬浮液,可根据本领域已知技术,使用适合的分散剂或湿润剂(如Tween 80)及悬浮剂来配制。无菌可注射的配制液可为无菌可注射的溶液或是悬浮于无毒的非口服注射稀释液或溶剂中,例如1,3-丁二醇的溶液。可使用的可接受载体及溶剂为甘露醇(mannitol)、水、林格氏溶液(Ringer’ssolution)或等渗透的氯化钠溶液。除此之外,非挥发油是常用的溶剂或是悬浮介质(例如:合成单甘油酯或双甘油酯)。脂肪酸如油酸 (oleic acid)与其甘油酯衍生物,亦可用于制备注射剂;天然医药可接受的油,例如橄榄油或蓖麻油,特别是其多氧乙基化的形态,同样可用于制备。这些油酯溶液或悬浮液,可包含长链醇类稀释液或分散剂、羧甲基纤维素或类似的分散剂。其它常用的表面活性剂,如Tween或Spans或其它类似乳化剂或一般医药制造业所使用于医药可接受的固态、液态或其它可用于剂型开发目的的剂量形式的生物可利用增强剂。
用于口服给药的组合物可为任何一种口服可接受的剂型,包括胶囊、锭片、乳化液与水悬浮液、分散液与溶液,但不限于此。以锭片为例,一般所使用的载体为乳糖或是玉米淀粉,润滑剂(如硬脂酸镁)亦常被添入其中。以口服胶囊给药形式而言,可用的稀释剂包括乳糖与干燥玉米淀粉。当以水悬浮液或乳化液经口给药时,活性成分可悬浮或是溶解于混有乳化剂或悬浮剂的油状界面中。如果需要,可添加适度的甜味剂、风味剂或是色素。鼻用气化喷雾剂或吸入剂组合物,可根据医药剂型领域中已知技术进行制备。含化合物的组合物亦可以栓剂方式进行直肠给药。
医药组合物的载体必须为「可接受性的」,即其必须与组合物的活性主成份兼容(较佳的是能稳定活性主成份),并且不能对被治疗的试体造成伤害。例如,一种或多种能与化合物形成溶解性更佳的复合物的溶解剂,也可用为传递该活性化合物的医药载体。其它载体举例包括胶质氧化硅、硬脂酸镁、纤维素、月桂硫酸钠与D&C黄色10号。
下述对于DBPR110的具体实例仅用以描述,并非意图以任何方式限制本发明的公开内容。无需进一步详细说明,本领域的技术人员根据本发明的内容而完整地利用本发明。本发明中所引用的文献内容均并入本发明中以供参详。
材料与方法
(1)E.coli及酵母菌菌株。购自OverExpress Inc的冷冻的感受态E.coli菌株C41,是由BL21(DE3)(43)衍生而来。使用标准酵母菌培养基及转化方法。S. cerevisiaeYPH857购自ATCC。YPH857的基因型是MATα ade2-101 lys2-801 ura3- 52 trp1-Δ63 HIS5CAN1 his3-Δ200 leu2-Δ1 cyh2。酵母菌感受态细胞是利用醋酸锂 (lithium acetate)制备。
(2)细胞培养及HCV抑制剂。Huh-7.5细胞及其衍生的HCV复制子细胞株 (HCVreplicon cell lines)培养于Dulbecco改良的Eagle’s培养基(DMEM,Gibco/BRL),培养环境为37℃、5%CO2。上述培养基中添加100U/mL青霉素-链霉素 (Gibco/BRL)、0.1mM非必需氨基酸(NEAA,Gibco/BRL)以及10%热失活胎牛血清 (FBS)。该HCV复制子细胞株分离自Lohman et al于Science 285:110-3(1999)中所记载的细胞株。除非另有说明,用于上述HCV复制子细胞株的培养液另外添加 0.25至0.5mg/mL的G418。化合物DBPR110及索非布韦(sofosbuvir)由台湾的国家卫生研究院生技与药物研究所合成。特拉普韦(Telaprevir)(Lin et al.,Antimicrob Agents Chemother,50:1813-22(2006))购自Acme Biosciences(Belmont,CA)。该化合物以10至500mM溶于二甲基亚砜(DMSO)作为储备溶液存放于-20℃直到进行测试。IFN-α购自Calbiochem(La Jolla,CA)并存放于-80℃。
(3)对HCV复制子的抑制分析。于96孔或12孔培养盘中,分别种入1×104细胞/孔密度(高通量筛选测定法)或1×105细胞/孔密度(经常测定)的细胞,并培养4小时。接着将该培养基吸除并以0.1mL(96孔盘)或1mL(12孔培养盘)的完全培养基取代,该完全培养基中包括连续浓度的单一化合物或组合化合物。将包括有化合物的培养盘培养72小时后进行荧光素酶表达(Promega)测试。分别测得每一化合物的EC50并据此确定用于组合实验的浓度范围。所有的实验数据均由独立的三次实验的平均值±标准差(SD)表示。选择指数(SI)是根据CC50对 EC50的比值计算而得。
(4)细胞毒性测试。细胞株对于抑制剂的灵敏度是利用3-(4,5-二甲基吡啶-2-基)-2,5-二苯基溴化镁(MTT)法分析测得。简言之,将Huh-7.5细胞株以1×105细胞 /孔密度种入包含有1mL培养基的12孔培养盘中并培养4小时。加入连续稀释的化合物或DMSO(阴性对照组),并接着将该培养盘另外再培养72小时。于各孔中加入MTT药剂后,再将培养盘于37℃、湿润的5%CO2环境下培养3小时,然后以ELISA盘式分析仪以波长563nm分析。所有的实验数据均由独立的四次实验的平均值±标准差(SD)表示。
(5)小分子抑制HCV的感染性。为了探讨DBPR110对于HCV颗粒形成的抑制性,利用如前所述的荧光素酶活性分析分别测定经DBPR110处理细胞及未经处理细胞的HCV复制子。参考譬如Wakita et al.,Nat Med 11:791-6(2005);以及 Zhang et al.,AntimicrobAgents Chemother 52:666-74(2008)。将衍生自全长HCV2a JFH1感染性cDNA纯系的体外(in vitro)转录RNA与荧光素酶报导基因结合,并透过电穿孔技术将其送入Huh-7.5细胞株中。该细胞以每孔1×105细胞/孔密度种入 12孔培养盘,并培养4小时。将培养基吸除并以1mL的完全培养基取代,该完全培养基中包括连续浓度的DBPR110。将具有化合物的培养盘培养72小时后,再将其培养基用以感染Huh-7.5细胞。感染前,将Huh-7.5细胞种于12孔培养盘 (1×105细胞/孔),含有10%FBS的DMEM中24小时。将每孔包括有HCV细胞培养基(HCVcc)的上清液加入至Huh-7.5细胞株中。于37℃培养72小时之后,将所有的细胞裂解物进行荧光素酶表达测定。
(6)分离抗药性复制子。由分别生长于包括0.2或200nM及60nM或1μM的 DBPR110的培养基中的HCV基因型1b Con1及2a JFH1复制子细胞株筛选出抗药性复制子细胞株。于0.2至0.4mg/mL的G418存在的情况下,将包含化合物的培养基加至单层的HCV1b-neo复制子细胞株约25%的细胞集合。将培养于二甲亚砜(DMSO)的复制子细胞株作为对照组。40天后,以TRIzol试剂(Invitrogen, Carlsbad,CA)并根据生产商说明书指示,由对照组复制子细胞及包括化合物的均相细胞株(homogeneous cell lines)中分离出总RNA。上述RNA以逆转录-PCR(RT- PCR)扩增。NS3-NS5B的RNA产物以凝胶加以纯化并亚克隆(subclone)至pRS-Luc- HCV1bRep载体,以于酵母菌中利用同源重组取代亲代NS3-NS5B。由上述酵母菌中,将36个纯系的质粒纯化并于E.coli C41菌株中再次扩增以进行DNA序列分析。
(7)构建包括抗药性突变的分子纯系。为了制备源自抗药性纯系的点突变,利用PCR以个别地或组合地将以下氨基酸置换P58S、P58T、P58L、Y93H、 Y93N、Y93C、V153M、M202L及M265V导入phRlu-HCV1b质粒中,且将 -T24A、P58L、Y93N及Y93H导入HCV2a质粒中。将上述PCR产物以凝胶纯化并利用重叠PCR连接以形成包括如下的单一、双重或三重突变的片段,以利用同源重组方式与直线型phRlu-HCV1b质粒(以HpaI切割)结合: V153M+M202L+M265V、Y93N+V153M+M202L+M265V及 Y93H+V153M+M202L+M265V。该些突变复制子质粒由酵母菌中纯化,并接着在 E.coli C41菌株再次扩增并维持。所有的构建体进行测序以确认所欲的突变存在,且确保没有其它的突变产生。
(8)RNA转录及暂时性复制子分析。利用经ScaI切割的DNAs及T7 MegaScript转录试剂盒(Ambion)根据生产商说明书指示,于体外(in vitro)合成RNA 转录物。进行暂时性复制子分析以定量经化合物所介导的病毒转译抑制(Dears et al.,J Virol 79:4599-609(2005))。透过如前所述的电穿孔将RNA转录物转染至Huh- 7.5细胞株。参考譬如Blight etal.,J Virol 76:13001-14(2002)。将一特定浓度的 DBPR110或对照组培养基加入每一培养盘的孔中,并分析细胞以测定转染4小时及72小时后的荧光素酶活性。将该些细胞裂解以进行发光测定法 (luminometry),且该荧光素酶测定法是通过混合5μl裂解物及25μl的Renilla荧光素酶检测试剂(Promega)来进行。为了定量由化合物所介导的抑制效果,由未经任何药物处理的细胞(Mock-treated)所产生的相对荧光素酶活性定义为100%(Zou etal., Virology 384:242-52(2009))。
(9)血清阻滞分析(Serum shift assay)。于血清阻滞分析中,DBPR110的抑制活性是利用复制子1b于10、20、30、40或50%胎牛血清或10或40%胞外正常人类血清的存在下测定。在不存在DBPR110或存在连续稀释DBPR110的情况下,于72小时培养后,通过与对照组相比,其Renilla荧光素酶活性(分别为EC50或 EC90)的50%或90%下降率而测得抑制率。
(10)能量计算。Accelrys公司(San Diego,CA)的Insight II程序中实施的模块对接(docking module)用以计算DBPR110与HCV NS5A变异体之间的结合能。氢原子首先被加入至该化合物及蛋白质中。对DBPR110及HCV NS5A变异体的位能是透过一致力场(Consistent Force Field(CFF))随后被分配。将利用CFF力场的分配位能的参数设为默认值。于DBPR110及HCV NS5A变异体之间的交互作用能、范德华力与静电力的组合最后利用Insight II程序中的模块对接计算而得。
(11)计算模型。Accelrys公司(San Diego,CA)的Discovery Studio 2.1程序用以建构HCV NS5A蛋白质的计算模式。亲代HCV NS5A的三维结构用以作为模板以进行能量的最小化。该结构的力场进一步利用CHARMm程序(Chemistry at HARvard MolecularMechanics)验证,且其中所使用的参数设定为默认值。
(12)统计分析。报告中的数值是三次独立测量值的平均值,并以平均值±标准差表示。实验组平均值之间的统计学的显著差异是通过对未配对数据以t检验 (Student t)进行测定。当P值<0.05时,则之间的差异视为具有统计上的显著差异 (Sigma Plot 10软件,Systat Software,San Jose,California)。
(13)抑制剂组合研究。利用与荧光素酶报导子相连的HCV复制子测定法评估DBPR110与IFN-α、利巴韦林(ribavirin)、NS3蛋白酶抑制剂(特拉普韦 (telaprevir)及波西普韦(boceprevir))以及NS5B核苷酸抑制剂(sofosbuvir)组合使用的效力。关于组合指数模型(combination index model),是将细胞与低于其细胞毒性的浓度、连续稀释的IFN-α、ribavirin、特拉普韦(telaprevir)、波西普韦(boceprevir) 或索非布韦(sofosbuvir),以及DBPR110培养72小时。CalcuSyn(BIOSOFT)用以分析由72小时荧光素酶为基准的HCV复制子测定法所获得的实验数据,并量化观察到的效果与预测值之间的差异。化合物的交互作用及浓度比例是利用Chou及 Talalay描述的方法量化。协同作用及加乘作用的程度是利用中效原理与组合指数 (CI)的计算进行评估。亦测定于EC50、EC70及EC90的组合指数(CIs)。总共对六种组合进行评估,每个条件进行三至八次重复实验测试。一般而言,CI为0.9则视为协同,CI>0.9或<1.1则视为加乘,而CI>1.1则为拮抗。
DBPR110是有潜力的HCV复制子抑制剂
DBPR110是一种新颖的二噻唑(di-thiazole)类似物,可做为HCV抑制子的抑制剂,且对于HCV1b及2a复制子细胞株,其EC50落于皮穆尔(picomolar)范围。 DBPR110对于基因型1b及2a复制子以及2a感染性病毒均展现改善效力,以荧光素酶报导子活性分析计算CC50均超过50μM,且EC50值分别为3.9、228.8及 18.3pM。如下表1所示。DBPR110对于HCV基因型1b复制子所展现的体外(in vitro)选择指数(CC50/EC50)超过12,800,000;对于基因型2b复制子则是173,130;且对于2a感染性病毒是720,461。此外,基因型1b对于DBPR110的敏感性比基因型2a复制子细胞对于DBPR110的敏感性大74倍。另一二咪唑类似物HCV抑制剂,BMS-790052,具有媲美抗HCV1b(EC50=9pM)及2a复制子活性(EC50=71 pM)的效力(Gao et al.,Nature 465:96-100(2010))。通过实时聚合酶链锁反应(real-time PCR)分析DBPR110的效力亦获得同样的结果。
为了区隔抑制病毒转录抑制与RNA合成抑制,监控报导基因表达程度的下降率以作为DBPR110抑制活性的指标。HCV1b报导复制子构建,pRS-Luc- HCV1bRep,是于体外(invitro)转录并转染至Huh7.5细胞中。于转染超过72小时后多次监控荧光活性。缺乏DBPR110时,荧光活性可维持直到转染72小时之后。该荧光活性的最大值出现于转染后8小时及72小时内,分别代表病毒复制及RNA复制。于转染后4、8、24、48及72小时测得荧光活性。转染后4及8小时,DBPR110对于Rluc信号具有最小的效果,然而该信号分别于转染24、48及 72小时后显著地下降(P<0.001)。总言之,本实验结果证实DBPR110显著地抑制病毒RNA的合成。
表1、DBPR110对于HCV复制子细胞株及病毒颗粒形成的效力
a平均值±标准差是以亲代细胞株为依据(n≥3)。
分离并鉴定抗DBPR110的基因型1b复制子
为了探讨DBPR110的抗药性图谱,于G418存在下培养HCV基因型1b复制子细胞并增加DBPR110的浓度为EC50值的50至50,000倍以获得抗DBPR110的纯系。选择实验显示同源复制子对于DBPR110的抑制效果具有抗药性,且与亲代细胞株相比失去其效力。与EC50值为0.0039nM的亲代细胞相比,抗DBPR110 的细胞株(即DBPR110R)具有14,000倍以上的抗药性,其EC50值为55nM以上。
由1b抗药性细胞株的包括NS3-NS5B的纯系的个别直接DNA测序显示, NS5A的N端表现出多个突变(总结于下表3)。P58L/T(20%)、Y93N/H(73%)、 V153M(53%)、M202L(47%)及M265V(40%)是于抗0.2nM DBPR110的纯系选择中所观察到的主要的基因突变。如下表2所示。总言之,由经200nM DBPR110处理细胞所分离的100%cDNA纯系包括Y93N、V153M、M202L及M265V突变。再参照下表2。由经DMSO处理的细胞所分离的NS5A cDNA纯系并未观察到上述氨基酸置换。于NS5A的P58及Y93的置换是HCV抗药性研究中常见的突变,表示上述位置于HCV的抗药性功能方面扮演重要的角色。另一常见的突变是DBPR110HCV复制子细胞株的抗5’UTR、3’UTR以及其它非结构性区域。于 NS5A区域外则未发现上述突变。
表2、由对0.2或200nm的DBPR110产生抗药性的细胞所衍生的基因型1b HCV的HCVNS5A的氨基酸改变
ap表示衍生自抗DBPR110的个体纯系的质粒。
验证负责抗药表型的基因型1b突变
为了探讨特定突变对于抑制剂敏感性所造成的影响,具抗药性的表型进一步通过于包含荧光报导基因HCV基因型1b复制子中设计突变以验证,其可在暂时性报导分析中以监控复制。亲代及突变纯系的复制子的复制是于存在或缺乏 DBPR110的情况下随时间监控。对于亲代及突变株RNAs而言,最大复制效率于转染后72小时发生。
如下表3所示,在72小时,P58S、P58T、P58L、Y93N、Y93H及Y93C复制子的复制效率,分别是亲代复制子程度的42±10、40±15、19±8、8±3、8±4 及9±6%。该实验结果显示上述抗药性突变株适应性降低,且Y93N/H/C氨基酸置换表现出最低的复制能力。再次参照表3。先前已显示93残基的置换也对于复制适应性有重大影响。参考Fridell et al.,Antimicrob Agents Chemother 54:3641-50。 V153M、M202L及M265V的复制效率分别为亲代复制子程度的70±17、106±37 及87±23%,代表V153M、M202L及M265V突变不影响适应性。如表3所示。本实验数据显示大部分的抗DBPR110纯系,于58、93、153、202或265残基包括两种或四种氨基酸取代组成。如上表2所示。
该抗药性的复杂性是通过个别的cDNA纯系加以分析。所有的200nM抗 DBPR110纯系包括Y93N+V153M+M202L+M265V的组合。见上表2。此外,为了探讨与各种基因型相关的突变,针对具有如下组合的复制子进行暂时性复制子分析:V153M+M202L+M265V、Y93N+V153M+M202L+M265V及Y93H+ V153M+M202L+M265V。相对于亲代纯系,上述Y93N+V153M+M202L+M265V及Y93H+V153M+M202L+M265V变异体表现出16-32%的复制子破坏能力。如下表3所示。
各别氨基酸置换P58S/T/L及Y93N/H/C对DBPR110展现出不同程度的抗药性,其EC50值相对于亲代细胞株增加了25至2,547倍。如下表 3所示。当于同样的复制子中,Y93N与V153M、M202L及M265V组合时,对抑制剂大幅度提升2,547倍的抗药性。另一方面,于单一NS5A cDNA纯系所辨识出的V153M、 M202L及M265V的单一突变并不影响DBPR110的效力,但Y93N+V153M+ M202L+M265V或Y93H+V153M+M202L+M265V的组合则分别产生18,217或 5,824倍的抗药性。再参照下表3。显见NS5A的初级结构,或复制复合物中 NS5A的初级结构,对于抑制剂敏感性是一主要因素,且对于抑制剂敏感性而言是最主要的决定因素,同时58、93、153、202及265残基是HCV基因型1b的抗药性的决定因素。
表3、基因型1b HCV NS5A氨基酸置换对DBPR110效力的影响
a由暂时性转染分析(n≥3)所定义的平均值±标准差
分离并分析抗DBPR110的基因型2a复制子
通过于G418存在下培养HCV基因型2a复制子细胞并将DBPR110的浓度增加为60至1000nM的范围以获得抗DBPR110的细胞纯系。于选择性实验中显示,同源的复制子复制对抗源自DBPR110的抑制效果,且与亲代细胞株相比失去其效力。由2a抗药性细胞的包括NS3-NS5B的个别纯系的直接DNA测序显示 NS5A的N端表现出多个突变,如下表4所示。更具体地,于抗60nM DBPR110 纯系选择中所观察到的主要突变为T24A(50%)及P58L(50%)。总言之,100%由经21μM DBPR110处理细胞所分离的cDNA纯系仅包括Y93H突变。由经 DMSO处理的细胞所分离的NS5A cDNA纯系并未观察到上述氨基酸置换。
表4、自抗60nM或1μm DBPR110细胞所衍生的基因型2a HCV NS5A的氨基酸改变
ap表示衍生自抗DBPR110的个体纯系的质粒。
确认负责抗药性表型的基因型2a的突变
于复制子暂时性转染分析测试中,T24A、P58L及Y93N/H突变降低了对 DBPR110的敏感性。如下表5所示,72小时后,T24A、P58L、Y93N及Y93H复制子的复制效率分别为亲代复制子的120±12、154±20、103±28及192±13%。上述结果显示该些抗药性突变并不减损适应性。该个体氨基酸置换T24A、 P58L、Y93N及Y93H对DBPR110展现程度不同的抗药性,且EC50值较对照组增加65至3,041倍,再参照下表5。Y93H置换对于DBPR110的敏感性影响最大。显示NS5A的初级结构对于基因型2a抑制剂敏感性而言是主要的决定因素,且 24、58及93残基亦是HCV基因型2a中抗药性筛选的决定因素。
表5、基因型2a HCV NS5A的氨基酸置换对DBPR110效力的影响
a由暂时性转染分析(n≥3)所定义的平均值±标准差。
DBPR110的蛋白质结合活性
使用胎牛血清(FBS)与标准人类血清(NHS)以探讨血清蛋白结合对DBPR110 活性的影响。结果显示于10、20、30、40及50%FBS存在的情况下,EC50值分别为4.3±0.8、8.1±1.6、7.9±0.9、13.2±1.7及21.5±10pM,且EC90值分别为9.3 ±3.4、23.8±11、21.6±17、35.1±7.4及41.9±7.2pM。于10及40%NHS存在时, EC50值分别为33.5±0.4及210.9±6.3pM,且EC90值分别为41.6±1.3及588.1± 45.9pM。如下表6所示。在血清浓度高时,DBPR110的活性高于血清浓度低时,EC50及EC90值分别增加1.9至6.3倍及2.6至14.1倍。再参照下表6。上述结果显示于高血清浓度时,DBPR110效力具有明显的轻微转移(minorshift)。
表6、HCV1b复制子细胞株中,血清对于DBPR110的抗病毒活性的影响
a由亲代细胞株(n=3)所定义的平均值±标准差
bFBS,胎牛血清;NHS,正常人血清
结构研究
HCV NS5A突变与药物结合效力改变或抗药性有关。在此,使用计算模型以得到结构信息。应用HCV NS5A的三维结构(Love et al.,J Virol 83:4395-403(2009)) 及Discovery Studio 2.1程序(Accelrys,Inc),通过突变残基及最小化进行能量以建构模型。见下表7。与DBPR110相关的突变中,P58和Y93分别绘图于DBPR110- NS5A蛋白质复合体的HCV NS5A晶体结构上。此模型结果表示DBPR110直接结合于HCV NS5A的双聚体界面。
将HCV NS5A变异体中的DBPR110结合能是以一整体计算以更佳地了解抗 DBPR110变异体于与DBPR110交互作用时所扮演的角色。参见下表7。由 V153M伴随的亲代NS5A及NS5A展现与DBPR110最稳定的结构,其分别为 26.79及-29.06kcal mol-1的结合能(范德华力及静电力),其次是P58L,具有-4.38 kcal mol-1及Y93H的18.63kcal mol-1;而Y93N最不稳定,其具有79.30kcal mol-1的结合能。再次参见下表7。据此,上述残基的突变对DBPR110的亲合力产生影响。
表7、DBPR110抗药变异体的EC50及DBPR110对HCVNS5A的结合能
DBPR110与其它HCV抑制剂的组合疗法
对病毒的标准治疗或单一药剂疗法往往导致病毒亚型(quasi-species)产生,增加了临床药物抗药性的可能。因此,亟需更有效、耐受性更佳的联合疗法以降低病毒抗药性的出现。
为了评估DBPR110与其它HCV抑制剂组合使用的效果,利用基因型1b复制子编码的荧光素酶报导子基因以分析IFN-α、雷巴威林(ribavirin)、特拉普韦 (telaprevir)、波西普韦(boceprevir)或索非布韦(sofosbuvir)与DBPR110成对组合的抑制活性。于此系统中,DBPR110所计算的EC50值为3.3±0.8pM,而IFN-α、雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)及索非布韦(sofosbuvir)分别的EC50值为35.1±4.7IU/mL、20.5±3.5mM、301.6±2.8nM、360.6±19.9nM及 91.5±18.3nM。参见下表8。
表8、DBPR110、IFN-α、雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)及索非布韦(sofosbuvir)对HCV-1b复制子细胞株的效力
化合物 | EC<sub>50</sub><sup>a</sup> | EC<sub>90</sub><sup>a</sup> | CC<sub>50</sub><sup>a</sup> |
DBPR110(pM) | 3.3±0.8 | 7.4±0.8 | >50,000 |
IFN-α(IU/mL) | 35.1±4.7 | 327.0±0.01 | >2,000 |
Ribavirin(μM) | 20.5±3.5 | 95.0±20.1 | >200 |
特拉普韦(Telaprevir)(nM) | 301.6±2.8 | 911.9±75.4 | >5,000 |
波西普韦(Boceprevir)(nM) | 360.6±19.9 | 962.0±21.5 | >5,000 |
索非布韦(sofosbuvir)(nM) | 91.5±18.3 | 323.0±66.1 | >5,000 |
a由HCV 1b复制子细胞株(n≥3)所定义的平均值±标准差
DBPR110与IFN-α、雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)或索非布韦(sofosbuvir)于不同比例下混合,并且将随后产生的各混合物连续稀释。每一药物组合的抑制性是根据利用于50%、75%及90%的组合指数计算的中位效应原理(median effect principle)加以分析。于三次独立实验中,DBPR110 与IFN-α、雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)或索非布韦(sofosbuvir)的组合于50%、75%及90%的有效剂量时产生协同效应。参见下表 9。于该些实验中,DBPR110、IFN-α、雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)或索非布韦(sofosbuvir)所使用的浓度没有细胞毒性。
表9、50%、75%及90%有效剂量的DBPR110与IFN-α、雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)及索非布韦(sofosbuvir)组合的协同效应
a由HCV 1b复制子细胞株(n≥3)所定义的平均值±标准差
DBPR110与IFN-α及雷巴威林(ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)或索非布韦(sofosbuvir)的组合亦于三重药物组合中,利用基因型1b复制子细胞进行测试,如下表10所示。当利用三重药物组合时,于50%、75%及 90%的有效剂量观察到协同效应。参见下表10。
表10、50%、75%及90%有效剂量的DBPR110与IFN-α、雷巴威林 (ribavirin)、特拉普韦(telaprevir)、波西普韦(boceprevir)及索非布韦(sofosbuvir)组合的协同效应
a由HCV 1b复制子细胞株(n≥3)所定义的平均值±标准差
其它实施例
本发明所揭露的所有技术特征可任意组合。每一揭露于本发明中的技术特征可通过相同、等效或类似目的的替代技术特征加以替换。因此,除非另有说明,否则本发明中所揭示的技术特征仅为等效或类似特征的一个范例。
由上面的描述,本领域具有通常知识者可轻易地确认本发明的必要技术特征,且在不脱离本发明的精神及范围的前提下,可对本发明进行各种改变及修饰以使其适用于各种用途及条件。因此,其它的实施例亦包括于本发明权利要求书的范围之内。
上述实施例仅是为了方便说明而举例而已,本发明所主张的权利范围以权利要求书为准,而非仅限于上述实施例。
Claims (15)
1.一种治疗C型肝炎病毒的医药组合物,包括(a)有效剂量的两种HCV抑制剂,该HCV抑制剂由干扰素-α(IFN-α)和雷巴威林(ribavirin)、特拉普韦、波西普韦或索非布韦之一组成;以及(b)有效剂量的抗HCV化合物,其如式(I)所示:
其中,
A是
B是
每一R5及R6各自独立为H或F;
每一R11及R12各自为C3-C5环烷基;和
每一Y1和Y2各自独立为:被删除的、C(O)或C(O)O。
2.根据权利要求1所述的医药组合物,其中,该抗HCV化合物如式(III)所示:
3.根据权利要求1所述的医药组合物,其中,该抗HCV化合物为:
4.根据权利要求1所述的医药组合物,其中,该抗HCV化合物为:
5.根据权利要求1所述的医药组合物,其中,该干扰素-α(IFN-α)是聚乙二醇化的IFN-α。
6.根据权利要求4所述的医药组合物,其中,该干扰素-α(IFN-α)是聚乙二醇化的IFN-α。
7.根据权利要求1所述的医药组合物,其中每一R11及R12各自为C3-C5环丙基。
8.根据权利要求1所述的医药组合物,其中每一R11及R12各自为C3-C5环丁基。
9.根据权利要求1所述的医药组合物,其中每一R11及R12各自为C3-C5环戊基。
10.根据权利要求7所述的医药组合物,其中每一A及B各自为
11.根据权利要求7所述的医药组合物,其中A为和B为
12.根据权利要求1所述的医药组合物,其中所述两种HCV抑制剂为干扰素-α和雷巴威林。
13.根据权利要求1所述的医药组合物,其中所述两种HCV抑制剂为干扰素-α和特拉普韦。
14.根据权利要求1所述的医药组合物,其中所述两种HCV抑制剂为干扰素-α和波西普韦。
15.根据权利要求1所述的医药组合物,其中所述两种HCV抑制剂为干扰素-α和索非布韦。
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