CN110536682A - 依拉非诺或其衍生物与抗nash、抗纤维化或抗胆汁淤积药剂的组合 - Google Patents
依拉非诺或其衍生物与抗nash、抗纤维化或抗胆汁淤积药剂的组合 Download PDFInfo
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- CN110536682A CN110536682A CN201880025897.XA CN201880025897A CN110536682A CN 110536682 A CN110536682 A CN 110536682A CN 201880025897 A CN201880025897 A CN 201880025897A CN 110536682 A CN110536682 A CN 110536682A
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Abstract
本发明涉及一种组合产品及其治疗用途。
Description
技术领域
本发明涉及一种用于治疗炎性、代谢、纤维化和胆汁淤积性疾病的组合疗法。
背景技术
在WO2004005233中公开的1-[4-甲硫基苯基]-3-[3,5-二甲基-4-羧基二甲基甲氧基苯基]丙-2-烯-1-酮(伊拉非诺(Elafibranor)或ELA,以前被命名为GFT505),具有可能对大量胃肠科和肝脏疾病特别是胆汁淤积性疾病例如PBC(原发性胆汁性胆管炎)和PSC(原发性硬化性胆管炎)或肝病特别是非酒精性脂肪性肝病(NAFLD)例如非酒精性脂肪性肝炎(NASH)的治疗有利的性质。
在NASH中曾经进行过的最大的干预性研究之一,即为期1年的基于肝脏活检的2b期试验(GFT505-212-7)中,已试验了伊拉非诺在NASH中的临床效果。迄今为止已施用给超过800位患者和健康志愿者,伊拉非诺已证实了对NASH的有益性质,具体来说包括:改善肝功能异常的标志物包括ALAT、ASAT、γGT、ALP;改善胰岛素敏感度和葡萄糖稳态;对血浆脂类的有益效果,包括血浆甘油三酯和LDL-C的降低和HDL-C水平的提高;抗炎性质;在动物疾病模型中对组织学NASH参数(脂肪变性、炎症、纤维化)的功效,以及抗纤维化活性。在长达2年的致癌性研究的全套毒理学研究中,已确认了不存在安全性顾虑。伊拉非诺目前正在治疗NASH的3期临床研究中进行评估。也计划了在2期临床研究中评估这种分子用于PBC的治疗。
有鉴于它出色的治疗和药理学特性,伊拉非诺是一种非常有希望的分子,其可以潜在地用于组合药理方法中,以靶向参与大量炎性、代谢、纤维化和胆汁淤积性疾病的平行或互补的关键途径。
发明内容
本发明涉及一种组合产品,其包含:
(i)PPAR激动剂,特别是式(I)的化合物或其可药用盐:
其中:
Y1表示卤素、Ra或Ga-Ra基团;
A表示CH=CH或CH2-CH2基团;
Y2表示Gb-Rb基团;
Ga和Gb相同或不同,表示氧原子或硫原子;
Ra表示氢原子、未取代的(C1-C6)烷基、被一个或多个卤素原子、(C1-C6)烷氧基或(C1-C6)烷硫基取代的(C6-C14)芳基或(C1-C6)烷基、(C3-C14)环烷基、(C3-C14)环烷硫基或杂环基;
Rb表示至少被–COORc基团取代的(C1-C6)烷基,其中Rc表示氢原子、或未取代的或被一个或多个卤素原子取代的(C1-C6)烷基、(C3-C14)环烷基或杂环基;并且
Y4和Y5相同或不同,表示未取代的或被一个或多个卤素原子取代的(C1-C6)烷基、(C3-C14)环烷基或杂环基;
和
(ii)抗NASH、抗纤维化或抗胆汁淤积药剂。
在所述式(I)的化合物的特定实施方式中:
Y1表示卤素、Ra或Ga-Ra基团;
A表示CH=CH基团;
Y2表示Gb-Rb基团;
Ga和Gb相同或不同,表示氧原子或硫原子;
Ra表示(C1-C6)烷基或(C3-C14)环烷基,特别是未取代的或被一个或多个卤素原子取代的(C1-C6)烷基或(C3-C14)环烷基;
Rb表示被–COOR3基团取代的(C1-C6)烷基,其中Rc表示氢原子或具有1至4个碳原子的烷基;并且
Y4和Y5独立地表示(C1-C4)烷基。
在所述式(I)的化合物的特定实施方式中:
Y1表示Ra或Ga-Ra基团;
A表示CH2-CH2基团;
Y2表示Gb-Rb基团;
Ga表示氧原子或硫原子,并且Gb表示氧原子;
Ra表示(C1-C6)烷基或(C3-C14)环烷基;
Rb表示至少被–COORc基团取代的(C1-C6)烷基,其中Rc表示氢原子或(C1-C4)烷基;并且
Y4和Y5独立地表示(C1-C4)烷基。
在所述式(I)的化合物的特定实施方式中:
Y1表示卤素原子或Ra或Ga-Ra基团;
A表示CH2-CH2基团;
Y2表示Gb-Rb基团;
Ga表示氧原子或硫原子,并且Gb表示氧原子;
Ra表示被一个或多个卤素原子取代的(C1-C6)烷基或(C3-C14)环烷基;
Rb表示未取代的或被一个或多个卤素原子取代并且至少被–COORc基团取代的(C1-C6)烷基,其中Rc表示氢原子或(C1-C4)烷基;并且
Y4和Y5表示(C1-C4)烷基。
在所述式(I)的化合物的特定实施方式中,Gb是氧原子,并且Rb是被–COORc基团取代的(C1-C6)烷基,其中Rc表示氢原子或未取代的直链或支链(C1-C4)烷基。
在所述式(I)的化合物的特定实施方式中,Y1是(C1-C6)烷硫基,其包含直链或支链的未取代的或被一个或多个卤素原子取代的(C1-C6)烷基。
在特定实施方式中,所述式(I)的化合物选自1-[4-甲硫基苯基]-3-[3,5-二甲基-4-羧基二甲基甲氧基苯基]丙-2-烯-1-酮(伊拉非诺或GFT505)、1-[4-甲硫基苯基]-3-[3,5-二甲基-4-异丙氧基羰基二甲基甲氧基苯基]丙-2-烯-1-酮、1-[4-甲硫基苯基]-3-[3,5-二甲基-4-叔丁氧基羰基二甲基甲氧基苯基]丙-2-烯-1-酮、1-[4-三氟甲基苯基]-3-[3,5-二甲基-4-叔丁氧基羰基二甲基甲氧基苯基]丙-2-烯-1-酮、1-[4-三氟甲基苯基]-3-[3,5-二甲基-4-羧基二甲基甲氧基苯基]丙-2-烯-1-酮、1-[4-三氟甲氧基苯基]-3-[3,5-二甲基-4-叔丁氧基羰基二甲基甲氧基苯基]丙-2-烯-1-酮、1-[4-三氟甲氧基苯基]-3-[3,5-二甲基-4-羧基二甲基甲氧基苯基]丙-2-烯-1-酮、2-[2,6-二甲基-4-[3-[4-(甲硫基)苯基]-3-氧基-丙基]苯氧基]-2-甲基丙酸和2-[2,6-二甲基-4-[3-[4-(甲硫基)苯基]-3-氧基-丙基]苯氧基]-2-甲基-丙酸异丙酯。
在本发明的特定实施方式中,组分(ii)是抗NASH药剂。在本发明的实践中有用的说明性而非限制性的抗NASH药剂包括:
-乙酰CoA羧化酶抑制剂;
-腺苷A3受体激动剂;
-醛甾酮拮抗剂和盐皮质激素拮抗剂
-AMP激活的蛋白激酶刺激剂
-胰淀素受体激动剂和降钙素受体激动剂;
-血管生成素相关蛋白-3抑制剂
-抗LPS抗体;
-顶膜钠互相依赖性胆汁酸转运蛋白抑制剂;
-无水甜菜碱或RM-003;
-生物活性脂类;
-大麻素CB1受体拮抗剂;
-双重大麻素CB1受体/iNOS抑制剂
-半胱天冬酶抑制剂;
-组织蛋白酶抑制剂;
-CCR拮抗剂;
-CCR3趋化因子调节剂和嗜酸性粒细胞趋化因子2配体抑制剂
-二酰基甘油-O-酰基转移酶(DGAT)抑制剂
-二肽基肽酶IV(DPP4)抑制剂;
-胰岛素配体和胰岛素受体激动剂;
-胰岛素增敏剂和MCH受体-1拮抗剂
-NOX(NADPH氧化酶)抑制剂,例如双重NOX 1和4抑制剂;
-细胞外基质蛋白调节剂;
-硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物(FABAC);
-脂肪酸合酶(FAS)抑制剂
-成纤维细胞生长因子19(FGF-19)受体配体,例如重组成纤维细胞生长因子19(FGF-19)蛋白或FGF-19蛋白的有功能的工程化改造变体;
-成纤维细胞生长因子21(FGF-21)受体配体,例如成纤维细胞生长因子21(FGF-21)蛋白或FGF-21蛋白的有功能的工程化改造变体;
-法尼酯X受体(FXR)激动剂;
-半乳糖凝集素3抑制剂;
-胰高血糖素样肽-1(GLP-1)类似物和GLP-1受体激动剂;
-G蛋白偶联受体(GPCR)调节剂;
-G蛋白偶联受体84拮抗剂、结缔组织生长因子配体抑制剂和游离脂肪酸受体1激动剂,
-Hedgehog细胞信号传导途径抑制剂
-整合蛋白抑制剂;
-酮己糖激酶抑制剂白三烯(LT)/磷酸二酯酶(PDE)/脂氧合酶(LO)抑制剂;
-赖氨酰氧化酶同源物2抑制剂(LOXL2抑制剂);
-大环内酯类;
-甲基CpG结合蛋白2调节剂和转谷氨酰胺酶抑制剂;
-miRNA拮抗剂,
-线粒体载体家族抑制剂和线粒体磷酸盐载体蛋白抑制剂
-单克隆抗体;
-髓讨氧化物酶抑制剂;
-mTOR调节剂;
-NAD依赖性脱乙酰酶sirtuin刺激剂;PDE 5抑制剂
-烟酸受体(GPR109)激动剂
-核受体配体;
-P2Y13蛋白激动剂;
-苯丙氨酸羟化酶刺激剂;
-蛋白酶活化的受体(PAR)-2拮抗剂;
-蛋白激酶调节剂;
-PPARα激动剂;
-PPARγ激动剂;
-PPARδ激动剂;
-PPARα/γ激动剂;
-PPARα/δ激动剂;
-PPARγ/δ;
-PPARα/γ/δ激动剂或PPAR泛激动剂;
-Rho相关蛋白激酶2(ROCK2)抑制剂;
-钠-葡萄糖转运蛋白(SGLT)1抑制剂;
-钠-葡萄糖转运蛋白(SGLT)2抑制剂;
-硬脂酰CoA去饱和酶-1抑制剂;
-信号调控激酶1(ASK1)抑制剂;
-甲状腺受体β(THRβ)激动剂;
-Toll样受体2(TLR-2)拮抗剂;
-Toll样受体4(TLR-4)拮抗剂;
-I型自然杀伤T细胞抑制剂;
-酪氨酸激酶受体(RTK)调节剂;
-尿酸阴离子交换蛋白1抑制剂和黄嘌呤氧化酶抑制剂;
-血管黏附蛋白-1(VAP-1)抑制剂,和
-维生素D受体(VDR)激动剂。
在本发明的另一个特定实施方式中,组分(ii)是抗NASH药剂。
在特定实施方式中,所述抗NASH药剂选自:
-乙酰CoA羧化酶抑制剂;
-抗LPS抗体;
-顶膜钠互相依赖性胆汁酸转运蛋白抑制剂;
-生物活性脂类;
-大麻素CB1受体拮抗剂;
-双重大麻素CB1受体/iNOS抑制剂
-半胱天冬酶抑制剂;
-组织蛋白酶抑制剂;
-CCR拮抗剂;
-二酰基甘油-O-酰基转移酶(DGAT)抑制剂
-二肽基肽酶IV(DPP4)抑制剂;
-NOX(NADPH氧化酶)抑制剂,例如双重NOX 1和4抑制剂;
-细胞外基质蛋白调节剂;
-硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物(FABAC);
-成纤维细胞生长因子19(FGF-19)受体配体,例如重组成纤维细胞生长因子19(FGF-19)蛋白或FGF-19蛋白的有功能的工程化改造变体;
-成纤维细胞生长因子21(FGF-21)受体配体,例如成纤维细胞生长因子21(FGF-21)蛋白或FGF-21蛋白的有功能的工程化改造变体;
-法尼酯X受体(FXR)激动剂;
-半乳糖凝集素3抑制剂;
-胰高血糖素样肽-1(GLP-1)类似物;
-G蛋白偶联受体(GPCR)调节剂;
-整合蛋白抑制剂;
-白三烯(LT)/磷酸二酯酶(PDE)/脂氧合酶(LO)抑制剂;
-大环内酯类;
-miRNA拮抗剂,
-单克隆抗体;
-mTOR调节剂;
-核受体配体;
-P2Y13蛋白激动剂;
-蛋白酶活化的受体(PAR)-2拮抗剂;
-蛋白激酶调节剂;
-PPARα激动剂;
-PPARγ激动剂;
-PPARδ激动剂;
-PPARα/γ激动剂;
-PPARα/δ激动剂;
-PPARγ/δ;
-PPARα/γ/δ激动剂或PPAR泛激动剂;
-Rho相关蛋白激酶2(ROCK2)抑制剂;
-钠-葡萄糖转运蛋白(SGLT)2抑制剂;
-信号调控激酶1(ASK1)抑制剂;
-甲状腺受体β(THRβ)激动剂;
-Toll样受体4(TLR-4)拮抗剂;
-酪氨酸激酶受体(RTK)调节剂;
-血管黏附蛋白-1(VAP-1)抑制剂;和
-维生素D受体(VDR)激动剂。
其他抗NASH药剂包括KB-GE-001和NGM-386和NGM-395、NC-10以及TCM-606F。其他抗NASH药剂包括icosabutate、NC-101、NAIA-101、考来维仑和PRC-4016。
在本发明的特定实施方式中,组分(ii)是抗纤维化药剂。在本发明的实践中有用的说明性而非限制性的抗纤维化药剂包括:
-腺苷A3受体激动剂
-血管紧张肽II受体阻断剂
-靶向转化生长因子β2(TGF-β2)的反义寡核苷酸;
-生物活性脂类;
-半胱天冬酶抑制剂;
-大麻素CB2受体模拟物;
-双重法尼酯X受体(FXR)/TGR5激动剂;
-NOX(NADPH氧化酶)抑制剂,例如双重NOX 1和4抑制剂;
-半乳糖凝集素3抑制剂;
-Hedgehog细胞信号传导途径抑制剂
-免疫调节剂;
-整合蛋白抑制剂;
-巨噬细胞甘露糖受体调节剂;
-金属蛋白酶-9(MMP-9)刺激剂;
-单克隆抗体;
-NF-κB抑制剂;
-非甾类消炎药(NSAID)
-PDGFR调节剂;
-PPARα激动剂;
-PPARγ激动剂;
-PPARδ激动剂;
-PPARα/γ激动剂;
-PPARα/δ激动剂;
-PPARγ/δ;和
-PPARα/γ/δ激动剂或PPAR泛激动剂。
在另一个特定实施方式中,所述抗纤维化药剂选自:
-靶向转化生长因子β2(TGF-β2)的反义寡核苷酸;
-生物活性脂类;
-半胱天冬酶抑制剂;
-大麻素CB2受体模拟物;
-双重法尼酯X受体(FXR)/TGR5激动剂;
-NOX(NADPH氧化酶)抑制剂,例如双重NOX 1和4抑制剂;
-半乳糖凝集素3抑制剂;
-免疫调节剂;
-整合蛋白抑制剂;
-巨噬细胞甘露糖受体调节剂;
-金属蛋白酶-9(MMP-9)刺激剂;
-单克隆抗体;
-NF-κB抑制剂;
-非甾类消炎药(NSAID)
-PDGFR调节剂;
-PPARα激动剂;
-PPARγ激动剂;
-PPARδ激动剂;
-PPARα/γ激动剂;
-PPARα/δ激动剂;
-PPARγ/δ;和
-PPARα/γ/δ激动剂或PPAR泛激动剂。
其他抗纤维化药剂包括HEC-585、INV-240、RNAi治疗剂(Silence Therapeutics)和SAMiRNA计划(Bioneer Corp)。
其他说明性的抗纤维化药剂包括吡非尼酮或受体酪氨酸激酶抑制剂(RTKI)例如尼达尼布、索拉非尼和其他RTKI,或血管紧张肽II(AT1)受体阻断剂,或CTGF抑制剂,或易干扰TGFβ和BMP激活的途径的任何抗纤维化化合物,包括潜在的TGFβ复合体的激活剂例如MMP2、MMP9、THBS1或细胞表面整合蛋白、TGFβ受体I型(TGFBRI)或II型(TGFBRII)和它们的配体例如TGFβ、激活蛋白、抑制素、Nodal、抗苗勒管激素、GDF或BMP、辅助性共受体(也被称为III型受体),或SMAD依赖性经典途径的组分包括调节性或抑制性SMAD蛋白,或SMAD不依赖性或非经典途径包括MAPK信号传导的各个不同分支、TAK1、Rho样GTPase信号传导途径、磷脂酰肌醇-3激酶/AKT途径、TGFβ诱导的EMT过程或经典和非经典Hedgehog信号传导途径的成员包括Hh配体或靶基因,或易影响TGFβ的WNT或Notch途径的任何成员。
在本发明的特定实施方式中,组分(ii)是抗胆汁淤积药剂。在本发明的实践中有用的说明性而非限制性的抗胆汁淤积药剂包括:
-顶膜钠互相依赖性胆汁酸转运蛋白抑制剂(ASBTi);
-胆汁酸;
-组织蛋白酶抑制剂;
-CCR拮抗剂;
-CD40抑制剂;
-CD80抑制剂;
-NOX(NADPH氧化酶)抑制剂,例如双重NOX 1和4抑制剂;
-法尼酯X受体(FXR)激动剂;
-重组成纤维细胞生长因子(FGF)19;
-分形趋化因子配体抑制剂;
-回肠钠胆汁酸协同转运蛋白抑制剂;
-单克隆抗体;
-PPARα激动剂;
-PPARγ激动剂;
-PPARδ激动剂;
-PPARα/γ激动剂;
-PPARα/δ激动剂;
-PPARγ/δ;和
-PPARα/γ/δ激动剂或PPAR泛激动剂.
在特定实施方式中,所述抗胆汁淤积药剂选自:
-顶膜钠互相依赖性胆汁酸转运蛋白抑制剂(ASBTi);
-胆汁酸;
-组织蛋白酶抑制剂;
-CCR拮抗剂;
-CD40抑制剂;
-CD80抑制剂;
-NOX(NADPH氧化酶)抑制剂;
-法尼酯X受体(FXR)激动剂;
-重组成纤维细胞生长因子(FGF)19;
-分形趋化因子配体抑制剂;
-回肠钠胆汁酸协同转运蛋白抑制剂;
-单克隆抗体;
-PPARα激动剂;
-PPARγ激动剂;
-PPARδ激动剂;
-PPARα/γ激动剂;
-PPARα/δ激动剂;
-PPARγ/δ;
-PPARα/γ/δ激动剂或PPAR泛激动剂。
说明性的乙酰CoA羧化酶抑制剂包括但不限于GS-0976、ND-654、AC-8632、PF05221304、CP640186、吉卡宾(Gemcabene)、MK-4074和PF05175157。
说明性的腺苷A3受体激动剂包括但不限于2-(1-己炔基)-N-甲基腺苷、Piclidenoson CF-101(IB-MECA)、纳莫德森(Namodenoson)CF-102、2-Cl-IB-MECA、CP-532,903、肌苷、LUF-6000和MRS-3558。
说明性的醛甾酮拮抗剂和盐皮质激素受体拮抗剂包括但不限于阿帕拉酮(Apararenone)(MT 3995)、阿米洛利、螺内酯、依普利酮、坎利酮和坎利酸钾、孕酮、屈螺酮、孕二烯酮和贝尼地平。
说明性的AMP激活的蛋白激酶刺激剂包括但不限于PXL-770、MB-11055、Debio-0930B、甲福明、CNX-012、O-304、芒果苷钙盐、伊屈泼帕、carotuximab和Imeglimin。
说明性的胰淀素受体激动剂和降钙素受体激动剂包括但不限于KBP-042和KBP-089。
说明性的血管生成素相关蛋白-3抑制剂包括但不限于ARO-ANG3、IONIS-ANGGPTL3-LRx或AKCEA-ANGPTL3LRx、evinacumab和ALN-ANG。
根据本发明,当在本文中使用时,术语“1型血管紧张肽受体拮抗剂”包括但不限于厄贝沙坦。
根据本发明,当在本文中使用时,术语“抗LPS抗体”包括但不限于IMM-124-E。
说明性的靶向转化生长因子β2的反义寡核苷酸包括但不限于ASPH-0047、IMC-TR1和ISTH-0047。
说明性的顶膜钠互相依赖性胆汁酸转运蛋白抑制剂包括但不限于A-4250、伏昔巴特(volixibat)、以前称为SHP-625的马拉巴特(maralixibat)、GSK-2330672、elobixibat和CJ-14199。
说明性的胆汁酸包括但不限于奥贝胆酸(OCA)和UDCA、去甲熊去氧胆酸和熊去氧胆酸。
说明性的生物活性脂类包括但不限于5-羟基二十碳五烯酸(15-HEPE、DS-102)。
在另一个特定实施方式中,所述生物活性脂类可以选自不饱和脂肪酸例如25-花生四烯酸、二十碳五烯酸乙酯、二十碳五烯酸和二十二碳六烯酸。
说明性的大麻素CB1受体拮抗剂包括但不限于那马西佐单抗(namacizumab)、GRC-10801、MRI-1569、MRI-1867、DBPR-211、AM-6527:AM-6545、NESS-11-SM、CXB-029、GCC-2680、TM-38837、Org-50189、PF-514273、BMS-812204、ZYO-1、AZD-2207、AZD-1175、奥替那班、伊必那班、surinabant、利莫那班、屈那班、SLV-326、V-24343和O-2093。
说明性的大麻素CB2受体模拟物包括但不限于anabasum(Resunab、JKT-101)。
说明性的半胱天冬酶抑制剂包括但不限于恩利卡生(Emricasan)、belnacasan、nivocasan、IDN-7314、F-573、VX-166、YJP-60107、MX-1122、IDN-6734、TLC-144、SB-234470、IDN-1965、VX-799、SDZ-220-976和L-709049。
说明性的组织蛋白酶抑制剂包括但不限于VBY-376、VBY-825、VBY-036、VBY-129、VBY-285、Org-219517、LY3000328、RG-7236和BF/PC-18。
说明性的CCR拮抗剂包括但不限于CCR2/5拮抗剂例如塞尼克罗克(Cenicriviroc)、PG-092、RAP-310、INCB-10820、RAP-103、PF-04634817和CCX-872。
说明性的CD40抑制剂包括但不限于FFp-104、xl-050、DOM-0800、XmAb-5485、KGYY-15、FFP-106、TDI-0028和ABI-793。
说明性的CD80抑制剂包括但不限于RhuDex、FPT-155、ToleriMab、加利昔单抗、SCH-212394、IGM-001、ASP-2408和SCH-204698。
说明性的CCR3趋化因子调节剂和嗜酸性粒细胞趋化因子2配体抑制剂包括但不限于柏替木单抗、CM-101(人源化)、CM-102和RNS-60。
说明性的二酰基甘油-O-酰基转移酶抑制剂包括但不限于IONIS-DGAT2Rx(以前的ISIS-DGAT2Rx)、LY-3202328、BH-03004、KR-69530、OT-13540、AZD-7687、PF-06865571、PF-06424439和ABT-046。
说明性的二肽基肽酶IV抑制剂包括但不限于依格列汀、维达列汀、复格列汀、阿格列汀、沙格列汀、tilogliptin、阿拉格列汀、西他列汀、瑞格列汀、美格列汀、戈格列汀、曲格列汀、替格列汀、dutogliptin、利格列汀、吉格列汀、yogliptin、betagliptin、imigliptin、奥格列汀、维达列汀和denagliptin。
说明性的脂肪酸合酶(FAS)抑制剂包括但不限于TVB-2640、TVB-3664;、TVB-3166、TVB-3150、TVB-3199、TVB-3693BZL-101、2-十八炔酸、MDX-2、Fasnall、MT-061、G28UCM、MG-28、HS-160、GSK-2194069、KD-023、西洛他唑。
在特定实施方式中,所述FAS抑制剂是在下述化合物列表中选择的化合物:
和TVB-2640。
在另一个特定实施方式中,所述FAS抑制剂选自:
和TVB-2640。
在特定实施方式中,所述FAS抑制剂是TVB-2640。
说明性的双重法尼酯X受体(FXR)/TGR5激动剂包括但不限于INT-767。
说明性的NOX(NADPH氧化酶)抑制剂包括但不限于双重NOX1&4抑制剂、以前被称为GKT137831的GKT-831(2-(2-氯苯基)-4-[3-(二甲基氨基)苯基]-5-甲基-1H-吡唑并[4,3-c]吡啶-3,6(2H,5H)-二酮)和GKT-901。
说明性的细胞外基质蛋白调节剂包括但不限于CNX-024、CNX-025和SB-030。
说明性的法尼酯X受体(FXR)激动剂包括但不限于奥贝胆酸(OCA)、GS-9674、LJN-452或LJN452、LMB763、EDP-305、AKN-083、INT-767、GNF-5120、LY2562175、INV-33、NTX-023-1、EP-024297、Px-103and和SR-45023.。
说明性的分形趋化因子配体抑制剂包括但不限于E-6011和KAN-0440567。
说明性的成纤维细胞生长因子19(FGF-19)受体配体、重组成纤维细胞生长因子19(FGF-19)蛋白或FGF-19的有功能的工程化改造变体包括但不限于NGM-282。
说明性的成纤维细胞生长因子21(FGF-21)受体配体、成纤维细胞生长因子21(FGF-21)蛋白包括但不限于PEG-FGF21(以前的BMS-986036)、YH-25348、BMS-986171、YH-25723、LY-3025876和NNC-0194-0499。
说明性的半乳糖凝集素3抑制剂包括但不限于GR-MD-02、TD-139、ANG-4021、Galectin-3C、LJPC-201、TFD-100、GR-MD-03、GR-MD-04、GM-MD-01、GM-CT-01、GM-CT-02、Gal-100and和Gal-200。
说明性的胰高血糖素样肽-1(GLP-1)类似物包括但不限于索马鲁肽、利拉鲁肽、艾塞那肽、阿必鲁肽、度拉糖肽、利西拉肽、洛塞那肽、efpeglenatide、他司鲁泰、MKC-253、DLP-205和ORMD-0901。
说明性的胰高血糖素样肽-1(GLP-1)受体激动剂包括但不限于LY-3305677和长效胃泌酸调节素。
说明性的G蛋白偶联受体(GPCR)调节剂包括但不限于CNX-023。
说明性的G蛋白偶联受体84拮抗剂(GPR84拮抗剂)、结缔组织生长因子配体抑制剂和游离脂肪酸受体1激动剂(FFAR1激动剂)包括但不限于PBI-4050、PBI-4265、PBI-4283和PBI-4299。
说明性的Hedgehog细胞信号传导途径抑制剂包括但不限于维莫德吉(vismodegib)、TAK-441、IPI-926、Saridegib、索尼德吉/Erismodegib、BMS-833923/XL139、PF-04449913、Taladegib/LY2940680、ETS-2400、SHR-1539和CUR61414。
说明性的回肠钠胆汁酸协同转运蛋白抑制剂包括但不限于A-4250、GSK-2330672、伏昔巴特、CJ-14199和elobixibat。
说明性的免疫调节剂包括但不限于PBI-4050、PBI-4265、PBI-4283、PBI-4299和AIC-649。
说明性的胰岛素增敏剂和MCH受体-1拮抗剂包括但不限于MSDC-0602k、MSDC-0602、CSTI-100和AMRI。
说明性的整合蛋白抑制剂包括但不限于Pliant Therapeutic的整合蛋白抑制剂、Indalo Therapeutics的整合蛋白抑制剂、St Louis University的整合蛋白抑制剂、ProAgio和GSK-3008348。
说明性的酮己糖激酶抑制剂包括但不限于JNJ-28165722、JNJ-42065426、JNJ-42152981、JNJ-42740815、JNJ-42740828和PF-06835919。
说明性的白三烯/磷酸二酯酶/脂氧合酶抑制剂包括但不限于泰鲁司特(tipelukast)(以前的MN-001)、托鲁司特、硫鲁司特、马鲁司特、扎鲁司特、普鲁司特、孟鲁司特、吉姆司特(gemilukast)、维鲁司特、阿卡鲁司特(aklukast)、坡比司特(pobilikast)、西那司特和伊拉司特。
说明性的赖氨酰氧化酶同源物2抑制剂包括但不限于Rappaport、InterMune、Pharmaxis、AB-0023、Simtuzumab、PXS-5382A和PXS-5338。
说明性的大环内酯类包括但不限于索利霉素、阿奇霉素和红霉素。
说明性的巨噬细胞甘露糖受体调节剂包括但不限于AB-0023、MT-1001、[18F]FB18mHSA、Xemys、锝Tc 99m tilmanocept和CDX-1307。
说明性的甲基CpG结合蛋白2调节剂和转谷氨酰胺酶抑制剂包括但不限于半胱胺、EC半胱胺、肠溶包衣的半胱胺酒石酸氢盐、半胱胺酒石酸氢盐(肠溶包衣的)、Bennu、半胱胺酒石酸氢盐(肠溶包衣的)、Raptor、半胱胺酒石酸氢盐、DR半胱胺、延迟释放的肠溶包衣的半胱胺酒石酸氢盐、巯基乙胺、巯基乙胺(肠溶包衣的)、Bennu、巯基乙胺(肠溶包衣的)、Raptor、RP-103、RP-104、PROCYSBI和巯基乙胺(肠溶包衣的)。
说明性的miRNA拮抗剂包括但不限于RG-125(以前的AZD4076)、RGLS-5040、RG-101、MGN-5804,and和MRG-201。
说明性的金属蛋白酶-9(MMP-9)刺激剂包括但不限于Elastomics Ab的MMP-9刺激剂。
说明性的线粒体载体家族抑制剂和线粒体磷酸盐载体蛋白抑制剂包括但不限于TRO-19622、Trophos、奥利索西、RG-6083或RO-7090919。
说明性的髓讨氧化物酶抑制剂包括但不限于PF-06667272。
说明性的单克隆抗体(mAb)包括但不限于柏替木单抗、NGM-313、靶向IL-20的mAb、fresolimumab(抗TGFβ抗体)(以前的GC1008)、以前被称为BTT-1023的timolumab、那马西佐单抗、奥马珠单抗、雷珠单抗、贝伐单抗、lebrikizumab、依帕珠单抗、felvizumab、马妥珠单抗、monalizumab、瑞利珠单抗、foralumab(NI-0401、抗CD3抗体)、针对LOXL2的simtizumab(GS-6624)单抗、抗TNF抗体尤特克单抗和inebilizumab。
说明性的单克隆抗体选自抗IL20 mAb、抗TGFβ抗体、抗CD3抗体、抗LOXL2抗体和抗TNF抗体。
说明性的mTOR调节剂包括但不限于MSDC-0602和与SVP-西罗莫司共同施用的AAV基因疗法。
说明性的NAD依赖性脱乙酰酶sirtuin刺激剂、PDE 5抑制剂包括但不限于NS-0200。
说明性的NF-κB抑制剂包括但不限于LC-280126。
说明性的烟酸受体(GPR109)激动剂包括但不限于ARI-3037MO、MMF、LUF 6283、阿昔呋喃、IBC 293、MK-1903、GSK256073、MK-6892、MK-0354、SLx-4090、洛美他派、lexibulin、apabetalone、阿昔呋喃、拉罗匹仑、达珀利奈、安塞曲匹、INCB-19602、ST-07-02、洛美沙星、烟酸和控释/拉罗匹仑。
说明性的非甾类消炎药(NSAID)包括但不限于F-351、水杨酸酯(阿司匹林)、对乙酰氨基酚、丙酸衍生物(布洛芬、萘普生)、乙酸衍生物(吲哚美辛、双氯芬酸)、烯醇酸衍生物(吡罗昔康、苯基丁氮酮)、邻氨基苯甲酸衍生物(甲氯芬那酸、氟芬那酸)、选择性COX-2抑制剂(塞来昔布、帕瑞昔布)和磺酰苯胺类(尼美舒利)。
说明性的核受体配体包括但不限于DUR-928(以前的DV 928)。
说明性的P2Y13蛋白激动剂包括但不限于CER-209。
说明性的PDGFR调节剂包括但不限于BOT-501和BOT-191。
说明性的苯丙氨酸羟化酶刺激剂包括但不限于Pegvaliase、沙丙蝶呤、AAV-PAH、CDX-6114、墨蝶吟、RMN-168、ALTU-236、ETX-101、HepaStem、咯利普兰和前列地尔。
说明性的PPARα激动剂包括但不限于非诺贝特、环丙贝特、pemafibrate、吉非罗齐、氯贝丁酯、比尼贝特、克利贝特、氯贝酸、尼可贝特、皮利贝特、普拉贝脲、罗尼贝特、益多酯、托考贝特和SR10171。
说明性的PPARγ激动剂包括但不限于吡格列酮、氘化吡格列酮、罗格列酮、efatutazone、ATx08-001、OMS-405、CHS-131、THR-0921、SER-150-DN、KDT-501、GED-0507-34-Levo、CLC-3001和ALL-4。
说明性的PPARδ激动剂包括但不限于GW501516(Endurabol或({4-[({4-甲基-2-[4-(三氟甲基)苯基]-1,3-噻唑-5-基}甲基)硫]-2-甲基苯氧基}乙酸))、MBX8025(Seladelpar或{2-甲基-4-[5-甲基-2-(4-三氟甲基-苯基)-2H-[l,2,3]三唑-4-基甲基硫]-苯氧基}-乙酸)、GW0742([4-[[[2-[3-氟-4-(三氟甲基)苯基]-4-甲基-5-噻唑基]甲基]硫基]-2-甲基苯氧基]乙酸)、L165041、HPP-593和NCP-1046。
说明性的PPARα/γ激动剂(也被称为格列扎类)包括但不限于沙罗格列扎、阿格列扎、莫格列扎、替格列扎和DSP-8658。
除了伊拉非诺之外,说明性的PPARα/δ激动剂包括但不限于T913659。
说明性的PPARγ/δ激动剂包括但不限于共轭亚油酸(CLA)和T3D-959。
说明性的PPARα/γ/δ激动剂或“PPAR泛激动剂”包括但不限于IVA337(兰尼兰诺(Lanifibranor))、TTA(十四烷基硫代乙酸)、补骨脂二氢黄酮甲醚、GW4148、GW9135、苯扎贝特、洛贝格列酮和CS038。
说明性的蛋白酶活化的受体(PAR)-2拮抗剂包括但不限于PZ-235和NP-003。
说明性的蛋白激酶调节剂包括但不限于CNX-014、MB-11055、ALF-1、芒果苷、氨来占诺、GS-444217、REG-101和缬氨酸。
说明性的Rho相关蛋白激酶2(ROCK2)抑制剂包括但不限于KD-025、TRX-101、BA-1049、LYC-53976、INS-117548和RKI-1447。
说明性的信号调控激酶1(ASK1)抑制剂包括但不限于塞隆塞比(Selonsertib)(以前的GS-4997)。
说明性的钠-葡萄糖转运蛋白(SGLT)1抑制剂包括但不限于LX-4212/LX-4211/sotagliflozin、SAR-439954、LIK-066(Licoglifozin)、LX-2761、GSK-161235、LP-925219、KGA-2727、SAR-7226、SAR-474832、SY-008和AVX-3030。
说明性的钠-葡萄糖转运蛋白(SGLT)2抑制剂包括但不限于瑞格列净、达格列净、恩格列净、埃格列净、sotagliflozin、伊格列净、tianagliflozin、坎格列净、托格列净、janagliflozin、bexagliflozin、鲁格列净、舍格列净、HEC-44616、AST-1935和PLD-101。
说明性的硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物包括但不限于阿拉乔尔(Aramchol)、GRC-9332、steamchol、TSN-2998、GSK-1940029和XEN-801。
说明性的甲状腺激素受体β(THRβ)激动剂包括但不限于VK-2809、MGL-3196、MGL-3745、SKL-14763、sobetirome、BCT-304、ZYT-1、MB-07811和伊罗替罗。
说明性的Toll样受体2和4(TLR-2)拮抗剂包括但不限于CI-201,也被称为VB-201。
说明性的Toll样受体4(TLR-4)拮抗剂包括但不限于纳曲酮、也被称为纳美芬(Nalmefene)的JKB-121、M-62812、瑞沙托维、dendrophilin、CS-4771、AyuV-1、AyuV-25、NI-0101、EDA-HPVE7和eritoran。
说明性的I型自然杀伤T细胞抑制剂包括但不限于GRI-0621。
说明性的受体酪氨酸激酶(RTK)调节剂包括但不限于CNX-025、KBP-7018、尼达尼布和索拉非尼。
说明性的尿酸阴离子交换蛋白1抑制剂和黄嘌呤氧化酶抑制剂包括但不限于雷西奈德、RLBN-1001、verinurad、KUX-1151和雷西奈德+别嘌呤醇。
说明性的血管黏附蛋白-1(VAP-1)抑制剂也被称为含铜胺氧化酶2(AOC3),包括但不限于以前被称为PXS-4728A的BI-1467335、CP-664511、PRX-167700、ASP-8232、RTU-1096、RTU-007和BTT-1023。
说明性的维生素D受体(VDR)激动剂包括但不限于骨化醇、阿法骨化醇、1,25-二羟基维生素D3、维生素D2、维生素D3、骨化三醇、维生素D4、维生素D5、二氢速甾醇、钙泊三醇、他卡西醇1,24-二羟基维生素D3和帕立骨化醇。
根据本发明,术语“PPAR激动剂”是指过氧化物酶体增殖物活化受体激动剂,其是在脂类和葡萄糖稳态中发挥中心作用的一类药物。PPARα主要影响脂肪酸代谢,它的活化降低脂类水平,而PPARγ主要参与脂肪生成、能量平衡和脂类生物合成的调控。PPARδ参与脂肪酸氧化,主要是在骨骼肌和心肌中,但它也调控血液葡萄糖和胆甾醇水平。
在更特定实施方式中,所述式(I)的化合物是伊拉非诺或其可药用盐。
在本发明的组合产品的特定实施方式中:
-组分(i)是伊拉非诺或其可药用盐;并且
-组分(ii)选自GKT-831、阿拉乔尔、SHP-625、恩利卡生、沙罗格列扎、IMM-124-E、GS-9674、NGM-282、A-4250、GR-MD-02、GS-4997、F-351、索利霉素、瑞格列净、BTT-1023、IVA-337(兰尼兰诺)、JKB-121(纳美芬)、KD-025、MSDC-0602或MSDC-0602k、PBI-4050、PEG-FGF21、泰鲁司特、VK-2809、MGL-3196、GS-0976、RG-125、伏昔巴特、吡格列酮、索马鲁肽、GSK2330672、MBX-8025、CP-640186、塞隆塞比、GKT-831、PXS-4728A、维莫德吉、CF-102(纳莫德森)、MT-3995(阿帕拉酮)、二十碳五烯酸乙酯、KD-025、DUR-928和吉卡宾,特别是塞隆塞比、GKT-831、PXS-4728A、阿拉乔尔、PBI-4050、MSDC-0602k、VK-2809、MGL-3196、维莫德吉、CF-102(纳莫德森)、MT-3995(阿帕拉酮)、JKB-121(纳美芬)、恩利卡生、KD-025和DUR-928。
在本发明的组合产品的特定实施方式中:
-组分(i)是伊拉非诺或其可药用盐;并且
-组分(ii)选自GKT-831、阿拉乔尔、SHP-625、恩利卡生、沙罗格列扎、IMM-124-E、GS-9674、NGM-282、A-4250、GR-MD-02、GS-4997、LJN-452、F-351、索利霉素、瑞格列净、BTT-1023、IVA-337(兰尼兰诺)、JKB-121、KD-025、MSDC-0602、PBI-4050、PEG-FGF21、泰鲁司特、VK-2809、MGL-3196、GS-0976、颇得斯安、RG-125、伏昔巴特、吡格列酮、熊去氧胆酸、索马鲁肽、GSK2330672和MBX-8025,特别是阿拉乔尔、SHP-625、恩利卡生、沙罗格列扎、IMM-124-E、GS-9674、NGM-282、A-4250、GR-MD-02、GS-4997、LJN-452、F-351、索利霉素、瑞格列净、BTT-1023、IVA-337(兰尼兰诺)、JKB-121、KD-025、MSDC-0602、PBI-4050、PEG-FGF21、泰鲁司特、VK-2809、MGL-3196、GS-0976、RG-125、伏昔巴特、吡格列酮、熊去氧胆酸、索马鲁肽、GSK2330672和MBX-8025。
在本发明的组合产品的特定实施方式中:
-组分(i)是伊拉非诺或其可药用盐;并且
-组分(ii)选自GKT-831、阿拉乔尔、SHP-625、恩利卡生、沙罗格列扎、IMM-124-E、GS-9674、NGM-282、A-4250、GR-MD-02、GS-4997、F-351、索利霉素、瑞格列净、BTT-1023、IVA-337(兰尼兰诺)、JKB-121、KD-025、MSDC-0602、PBI-4050、PEG-FGF21、泰鲁司特、VK-2809、MGL-3196、GS-0976、颇得斯安、RG-125、伏昔巴特、吡格列酮、索马鲁肽、GSK2330672和MBX-8025。
在特定实施方式中,所述组合产品是ELA与GKT-831、ELA与塞隆塞比、ELA与GS-0976或ELA与颇得斯安的组合。
在特定实施方式中,所述组合产品是ELA与GS-0976、ELA与CP-640186、ELA与塞隆塞比、ELA与GKT-831(以前的GKT137831)、ELA与BI-1467335/PXS-4728A、ELA与阿拉乔尔、ELA与PBI-4050、ELA与MSDC-0602k、ELA与VK-2809、ELA与MGL-3196、ELA与维莫德吉、ELA与CF-102(纳莫德森)、ELA与MT-3995(阿帕拉酮)、ELA与JKB-121(纳美芬)、ELA与恩利卡生、ELA与KD-025、ELA与DUR-928或ELA与吉卡宾的组合。
在特定实施方式中,所述组合产品是ELA与塞隆塞比、ELA与GKT-831(以前的GKT137831)、ELA与BI-1467335/PXS-4728A、ELA与阿拉乔尔、ELA与PBI-4050、ELA与MSDC-0602k、ELA与VK-2809、ELA与MGL-3196、ELA与维莫德吉、ELA与CF-102(纳莫德森)、ELA与MT-3995(阿帕拉酮)、ELA与JKB-121(纳美芬)、ELA与恩利卡生、ELA与KD-025和ELA与DUR-928的组合。
在这个实施方式的另一个特定变化形式中,组分(ii)不是OCA或CVC。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)选自ACC抑制剂、ASK1抑制剂、双重NOX1和NOX4、VAP-1抑制剂、硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物、GPR84拮抗剂/FFAR1激动剂或免疫调节剂、mTOR调节剂或胰岛素增敏剂、THRβ激动剂、hedegehog信号传导途径抑制剂、腺苷A3受体激动剂、醛甾酮受体拮抗剂、TLR-4拮抗剂、半胱天冬酶抑制剂、ROCK2抑制剂和核受体配体。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是ACC抑制剂(特别是GS-0976或CP-640186或吉卡宾)、ASK1抑制剂(特别是塞隆塞比)、双重NOX1和NOX4抑制剂(特别是GKT-831,以前的GKT137831)、VAP-1抑制剂(特别是BI-1467335/PXS-4728A)、硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物(特别是阿拉乔尔)、GPR84拮抗剂/FFAR1激动剂或免疫调节剂(特别是PBI-4050)、mTOR调节剂或胰岛素增敏剂(特别是MSDC-0602k)、THRb激动剂(特别是VK-2809或MGL-3196)、hedegehog信号传导途径抑制剂(特别是维莫德吉)、腺苷A3受体激动剂(特别是CF-102(纳莫德森))、醛甾酮受体拮抗剂(特别是MT-3995(阿帕拉酮))、TLR-4拮抗剂(特别是JKB-121(纳美芬))、半胱天冬酶抑制剂(特别是恩利卡生)、ROCK2抑制剂(特别是KD-025)和核受体配体(特别是DUR-928)。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是ASK1抑制剂、双重NOX1和NOX4、VAP-1抑制剂、硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物、GPR84拮抗剂/FFAR1激动剂或免疫调节剂、mTOR调节剂或胰岛素增敏剂、THRβ激动剂、hedegehog信号传导途径抑制剂、腺苷A3受体激动剂、醛甾酮受体拮抗剂、TLR-4拮抗剂、半胱天冬酶抑制剂、ROCK2抑制剂和核受体配体。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是ASK1抑制剂(特别是塞隆塞比)、双重NOX1和NOX4抑制剂(特别是GKT-831,以前的GKT137831)、VAP-1抑制剂(特别是BI-1467335/PXS-4728A)、硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物(特别是阿拉乔尔)、GPR84拮抗剂/FFAR1激动剂或免疫调节剂(特别是PBI-4050)、mTOR调节剂或胰岛素增敏剂(特别是MSDC-0602k)、THRb激动剂(特别是VK-2809或MGL-3196)、hedegehog信号传导途径抑制剂(特别是维莫德吉)、腺苷A3受体激动剂(特别是CF-102(纳莫德森))、醛甾酮受体拮抗剂(特别是MT-3995(阿帕拉酮))、TLR-4拮抗剂(特别是JKB-121(纳美芬))、半胱天冬酶抑制剂(特别是恩利卡生)、ROCK2抑制剂(特别是KD-025)和核受体配体(特别是DUR-928)。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是ACC抑制剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是GS-0976、CP-640186或吉卡宾。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是GS-0976。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是CP-640186。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是吉卡宾。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是ASK1抑制剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是塞隆塞比。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是双重NOX1和NOX4抑制剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是GKT-831。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是VAP-1抑制剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是BI-1467335/PXS-4728A。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是阿拉乔尔。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是GPR84拮抗剂/FFAR1激动剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是PBI-4050。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是mTOR调节剂或胰岛素增敏剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)具体来说是MSDC-0602k。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是THRβ激动剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是VK-2809或MGL-3196。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是VK-2809。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是MGL-3196。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是Hedgehog细胞信号传导途径抑制剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是维莫德吉。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是腺苷A3受体激动剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是CF-102(纳莫德森)。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是醛甾酮受体拮抗剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是MT-3995(阿帕拉酮)。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是TLR-4拮抗剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是JKB-121(纳美芬)。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是核受体配体。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是恩利卡生。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是ROCK2抑制剂。
在更特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是KD-025。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是核受体配体。
在特定实施方式中,组分(i)是伊拉非诺或其可药用盐,并且组分(ii)是DUR-928。
在特定实施方式中,本发明的组合产品还包含至少一种其他治疗活性剂,其选自JAK/STAT抑制剂和其他抗炎性药剂和/或免疫抑制剂。
说明性的抗炎性和/或免疫抑制剂包括糖皮质激素类、NSAIDS、环磷酰胺、亚硝基脲类、叶酸类似物、嘌呤类似物、嘧啶类似物、氨甲喋呤、硫唑嘌呤、巯基嘌呤、环孢菌素、多球壳菌素、他克莫司、西罗莫司、霉酚酸衍生物、芬戈莫德和其他鞘氨醇-1-磷酸受体调节剂、针对诸如促炎性细胞因子和促炎性细胞因子受体、T-细胞受体和整合蛋白的靶的单克隆和/或多克隆抗体。
在另一个特定实施方式中,本发明的组合还可以包含至少一种具有已知抗纤维化活性的治疗活性药剂,例如吡非尼酮或受体酪氨酸激酶抑制剂(RTKI)例如尼达尼布、索拉非尼和其他RTKI,或血管紧张肽II(AT1)受体阻断剂,或CTGF抑制剂,或易干扰TGFβ和BMP激活的途径的任何抗纤维化化合物,包括潜在的TGFβ复合体的激活剂例如MMP2、MMP9、THBS1或细胞表面整合蛋白、TGFβ受体I型(TGFBRI)或II型(TGFBRII)和它们的配体例如TGFβ、激活蛋白、抑制素、Nodal、抗苗勒管激素、GDF或BMP、辅助性共受体(也被称为III型受体),或SMAD依赖性经典途径的组分包括调节性或抑制性SMAD蛋白,或SMAD不依赖性或非经典途径包括MAPK信号传导的各个不同分支、TAK1、Rho样GTPase信号传导途径、磷脂酰肌醇-3激酶/AKT途径、TGFβ诱导的EMT过程或经典和非经典Hedgehog信号传导途径的成员包括Hh配体或靶基因,或易影响TGFβ信号传导的WNT或Notch途径的任何成员。
在本发明的特定实施方式中,所述其他治疗活性药剂是PPAR激动剂。
在另一个特定实施方式中,所述PPAR激动剂是PPAR-α激动剂、PPAR-γ激动剂、PPAR-δ激动剂、PPAR-α/γ双重激动剂、PPARα/δ双重激动剂、PPARγ/δ双重激动剂或PPARα/γ/δ泛激动剂。
在特定实施方式中,所述其他治疗活性药剂是:
-至少一种PPAR-α激动剂;
-至少一种PPAR-γ激动剂;
-至少一种PPAR-δ激动剂;
-至少一种PPAR-α/δ双重激动剂;
-至少一种PPAR-α激动剂和至少一种PPARδ激动剂;
-至少一种PPAR-α/γ双重激动剂;
-至少一种PPAR-α激动剂和至少一种PPARγ激动剂;
-至少一种PPAR-γ/δ双重激动剂;
-至少一种PPAR-γ激动剂和至少一种PPARδ激动剂;
-至少一种PPAR-α/γ/δ泛激动剂;和
-至少一种PPAR-α激动剂、至少一种PPAR-γ激动剂和至少一种PPAR-δ激动剂。
在特定实施方式中,本发明的组合产品是包含如上所述的组分(i)和(ii)和可药用载体的组合物。
在特定实施方式中,所述组合产品是包含如上所述的组分(i)和(ii)的套装药剂盒,用于顺序、分开或同时使用。
在另一个实施方式中,组分(i)和(ii)被配制在注射用悬液、凝胶、油、丸剂、片剂、栓剂、粉剂、胶囊、气溶胶、软膏、霜剂、贴片或用于延长和/或缓慢释放的盖伦形式中。
本发明还涉及本发明的所述组合产品,其用作药物。
本发明还涉及本文公开的所述组合产品,其用于治疗疾病的方法中。在另一个实施方式中,本发明涉及一种治疗疾病的方法,所述方法包括向需要的对象施用治疗有效量的本文公开的组合产品。在另一个实施方式中,提供了本发明的组合产品的应用,其用于制造治疗疾病的药物。
具体来说,本发明的组合产品可用于治疗疾病例如免疫、炎性、代谢、纤维化和胆汁淤积性疾病。在特定实施方式中,所述疾病选自代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物引起的肝病、酒精引起的肝病、传染因子引起的肝病、炎性肝病、免疫系统功能障碍介导的肝病、血脂异常、心血管疾病、再狭窄、X综合征、代谢综合征、糖尿病、肥胖症、高血压、慢性胆管病变例如原发性硬化性胆管炎(PSC)、原发性胆汁性胆管炎(PBC)、胆道闭锁、3型进行性家族性肝内胆汁淤积症(PFIC3)、炎性肠病、克罗恩病、溃疡性结肠炎、瘢痕疙瘩、陈旧性心肌梗塞、硬皮病/系统性硬化症、炎性疾病、神经退行性疾病、癌症、肝癌、肝细胞癌、胃肠癌、胃癌、与神经纤维瘤病相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生性疾病、肥大细胞增多症、皮肤纤维肉瘤、实体肿瘤包括乳腺、肺、甲状腺或结肠直肠癌、前列腺癌、任何起源的肝纤维化或硬化、代谢疾病引起的肝纤维化或硬化、NAFLD引起的纤维化或硬化、NASH引起的纤维化或硬化、酒精引起的肝纤维化或硬化、药物引起的肝纤维化或硬化、传染因子引起的肝纤维化或硬化、寄生虫感染引起的肝纤维化或硬化、细菌感染引起的肝纤维化或硬化、病毒感染引起的纤维化或硬化、HBV感染引起的肝纤维化或硬化、HCV感染引起的肝纤维化或硬化、HIV感染引起的肝纤维化或硬化、HCV和HIV双重感染引起的肝纤维化或硬化、放疗或化疗引起的纤维化或硬化、胆道纤维化、由任何慢性胆汁淤积性疾病造成的肝纤维化或硬化、任何病因的消化道纤维化、克罗恩病引起的纤维化、溃疡性结肠炎引起的纤维化、肠(例如小肠)纤维化、结肠纤维化、胃纤维化、皮肤纤维化、表皮纤维化、内皮纤维化、由硬皮病/系统性硬化症造成的皮肤纤维化、肺纤维化、慢性炎性气道疾病例如COPD、哮喘、肺气肿、吸烟者的肺、肺结核继发的肺纤维化、肺纤维化、特发性肺纤维化(IPF)、心脏纤维化、肾纤维化、肾原性系统性纤维化、肌肉纤维化、软组织(例如纵隔膜或腹膜后腔)纤维化、骨髓纤维化、关节纤维化、肌腱纤维化、软骨纤维化、胰腺纤维化、子宫纤维化、神经系统纤维化、睾丸纤维化、卵巢纤维化、肾上腺纤维化、动脉纤维化、静脉纤维化、眼纤维化、心内膜心肌纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化(煤工尘肺的并发症)、增殖性纤维化、增生性纤维化、植入体周纤维化和石棉肺、关节纤维化、粘连性关节囊炎。
在最优选实施方式中,所述疾病选自代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物引起的肝病、酒精引起的肝病、传染因子引起的肝病、炎性肝病、免疫系统功能障碍介导的肝病、血脂异常、心血管疾病、再狭窄、X综合征、代谢综合征、糖尿病、肥胖症、高血压、慢性胆管病变例如原发性硬化性胆管炎(PSC)、原发性胆汁性胆管炎(PBC)、胆道闭锁、3型进行性家族性肝内胆汁淤积症(PFIC3)、炎性肠病、克罗恩病、溃疡性结肠炎、肝癌、肝细胞癌、胃肠癌、胃癌、结肠直肠癌、代谢疾病引起的肝纤维化或硬化、NAFLD引起的纤维化或硬化、NASH引起的纤维化或硬化、酒精引起的肝纤维化或硬化、药物引起的肝纤维化或硬化、传染因子引起的肝纤维化或硬化、寄生虫感染引起的肝纤维化或硬化、细菌感染引起的肝纤维化或硬化、病毒感染引起的纤维化或硬化、HBV感染引起的肝纤维化或硬化、HCV感染引起的肝纤维化或硬化、HIV感染引起的肝纤维化或硬化、HCV和HIV双重感染引起的肝纤维化或硬化、放疗或化疗引起的纤维化或硬化、胆道纤维化,由任何慢性胆汁淤积性疾病造成的肝纤维化或硬化、任何病因的消化道纤维化、克罗恩病引起的纤维化、溃疡性结肠炎引起的纤维化、肠(例如小肠)纤维化、结肠纤维化、胃纤维化、肺纤维化、慢性炎性气道疾病例如COPD、哮喘、肺气肿、吸烟者的肺、肺结核继发的肺纤维化、肺纤维化、特发性肺纤维化(IPF)。
另一方面,本发明涉及本发明的组合,其用于抑制负责胶原纤维的生产和/或负责细胞外基质的生产的成纤维细胞的增殖和/或活化。
根据本发明,术语“自身免疫疾病”被用于表示由对身体中正常存在的物质和组织的身体异常免疫应答引起的病症。所述疾病可能限于某些器官(例如在I型糖尿病或自身免疫性甲状腺炎中)或涉及不同位置中的特定组织(例如在古德帕斯彻氏病中,影响肺和肾中的基底膜)。
术语“炎症”被用于表示由涉及宿主细胞、血管和蛋白质和其他介导物的保护性应答引起的病症,所述保护性应答可能用于消除细胞/组织损伤的病因以及由最初的损害引起的坏死细胞/组织并启动修复过程。所述炎性反应可能表现为疼痛、发热、发红、肿胀、血管扩张、血流增加和功能丧失。
根据本发明,术语“纤维化”、“纤维化疾病”、“纤维化障碍”及其变化形式表示纤维性结缔组织在器官或组织中的过量沉积的病理状态。更具体来说,纤维化是一种病理过程,其包括作为对组织损伤的应答由结缔组织引起的持续性纤维化瘢痕形成和细胞外基质的过量生产。在生理上,结缔组织的沉积可以消除其下的器官或组织的体系结构和功能。
根据本发明,所述纤维化或纤维化障碍可能与任何器官或组织纤维化相关。特定器官纤维化的说明性而非限制性实例包括肝、消化道、肾、皮肤、表皮、内皮、肌肉、肌腱、软骨、心脏、胰腺、肺、子宫、神经系统、睾丸、阴茎、卵巢、肾上腺、动脉、静脉、结肠、肠(例如小肠)、胆道、软组织(例如纵隔膜或腹膜后腔)、骨髓、关节或胃纤维化,特别是肝、肾、皮肤、表皮、内皮、肌肉、肌腱、软骨、心脏、胰腺、肺、子宫、神经系统、睾丸、卵巢、肾上腺、动脉、静脉、结肠、肠(例如小肠)、胆道、软组织(例如纵隔膜或腹膜后腔)、骨髓、关节、眼或胃纤维化。
根据本发明,术语“胆汁淤积”或“胆汁淤积性疾病”或“胆汁淤积性障碍”及其变化形式表示由肝细胞分泌受损或胆汁通过肝内或肝外胆道的流动阻塞造成的胆汁流量的减少所定义的病理状况。因此,胆汁淤积的临床定义是其中正常分泌到胆汁中的物质被滞留的任何病症。
在特定实施方式中,所述纤维化障碍选自肝、消化道、肺、心脏、肾、肌肉、皮肤、软组织(例如纵隔膜或腹膜后腔)、骨髓、肠和关节(例如膝、肩或其他关节)纤维化。
在优选实施方式中,所述纤维化障碍选自肝、肺、皮肤、肾和肠纤维化。
在本发明的更优选实施方式中,治疗的纤维化障碍选自纤维化障碍得下述非穷举性名单:非酒精性脂肪性肝炎(NASH),肺纤维化,特发性肺纤维化,皮肤纤维化,眼纤维化(例如囊纤维化),心内膜心肌纤维化,纵隔纤维化,骨髓纤维化,腹膜后纤维化,进行性大块纤维化(煤工尘肺的并发症),增殖性纤维化,增生性纤维化,慢性炎性气道疾病(COPD、哮喘、肺气肿、吸烟者的肺、肺结核)继发的肺纤维化,酒精或药物引起的肝纤维化,肝硬化,感染引起的肝纤维化,放疗或化疗引起的纤维化,肾原性系统性纤维化,克罗恩病,溃疡性结肠炎,瘢痕疙瘩,陈旧性心肌梗塞,硬皮病/系统性硬化症,关节纤维化,某些形式的粘连性关节囊炎,慢性纤维化胆管病变例如原发性硬化性胆管炎(PSC)和原发性胆汁性胆管炎(PBC),胆道闭锁,3型进行性家族性肝内胆汁淤积症(PFIC3),植入体周纤维化和石棉肺。
胆汁淤积被定义为由肝细胞分泌受损(肝细胞性胆汁淤积)或胆汁通过肝内或肝外胆道的流动阻塞(阻塞性胆汁淤积)造成的胆汁流量的减少。在临床实践中,胆汁淤积是其中胆汁从肝脏的流动减缓或受阻的任何病症。根据本发明的特定实施方式,所述胆汁淤积性疾病选自原发性胆汁性胆管炎(PBC)、原发性硬化性胆管炎(PSC)、妊娠期肝内胆汁淤积症、进行性家族性肝内胆汁淤积症、胆管闭锁、胆石病、感染性胆管炎、与朗格汉斯细胞组织细胞增多症相关的胆管炎、艾欧吉勒综合征、非综合征型胆管缺失、药物引起的胆汁淤积症和与全肠胃外营养相关的胆汁淤积症。在优选实施方式中,所述胆汁淤积性疾病PBC或PSC,特别是PBC。
炎性疾病、纤维化疾病、代谢疾病和胆汁淤积性疾病的实例包括代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物引起的肝病、酒精引起的肝病、传染因子引起的肝病、炎性肝病、免疫系统功能障碍介导的肝病、血脂异常、心血管疾病、再狭窄、X综合征、代谢综合征、糖尿病、肥胖症、高血压、慢性胆管病变例如原发性硬化性胆管炎(PSC)、原发性胆汁性胆管炎(PBC)、胆道闭锁、3型进行性家族性肝内胆汁淤积症(PFIC3)、炎性肠病、克罗恩病、溃疡性结肠炎、瘢痕疙瘩、陈旧性心肌梗塞、硬皮病/系统性硬化症、炎性疾病、神经退行性疾病、癌症、肝癌、肝细胞癌、胃肠癌、胃癌、与神经纤维瘤病相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生性疾病、肥大细胞增多症、皮肤纤维肉瘤、实体肿瘤包括乳腺、肺、甲状腺或结肠直肠癌、前列腺癌、任何起源的肝纤维化或硬化、代谢疾病引起的肝纤维化或硬化、NAFLD引起的纤维化或硬化、NASH引起的纤维化或硬化、酒精引起的肝纤维化或硬化、药物引起的肝纤维化或硬化、传染因子引起的肝纤维化或硬化、寄生虫感染引起的肝纤维化或硬化、细菌感染引起的肝纤维化或硬化、病毒感染引起的纤维化或硬化、HBV感染引起的肝纤维化或硬化、HCV感染引起的肝纤维化或硬化、HIV感染引起的肝纤维化或硬化、HCV和HIV双重感染引起的肝纤维化或硬化、放疗或化疗引起的纤维化或硬化、胆道纤维化、由任何慢性胆汁淤积性疾病造成的肝纤维化或硬化、任何病因的消化道纤维化、克罗恩病引起的纤维化、溃疡性结肠炎引起的纤维化、肠(例如小肠)纤维化、结肠纤维化、胃纤维化、皮肤纤维化、表皮纤维化、内皮纤维化、由硬皮病/系统性硬化症造成的皮肤纤维化、肺纤维化、慢性炎性气道疾病例如COPD、哮喘、肺气肿、吸烟者的肺、肺结核继发的肺纤维化、肺纤维化、特发性肺纤维化(IPF)、心脏纤维化、肾纤维化、肾原性系统性纤维化、肌肉纤维化、软组织(例如纵隔膜或腹膜后腔)纤维化、骨髓纤维化、关节纤维化、肌腱纤维化、软骨纤维化、胰腺纤维化、子宫纤维化、神经系统纤维化、睾丸纤维化、卵巢纤维化、肾上腺纤维化、动脉纤维化、静脉纤维化、眼纤维化、心内膜心肌纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化(煤工尘肺的并发症)、增殖性纤维化、增生性纤维化、植入体周纤维化和石棉肺、关节纤维化、粘连性关节囊炎。
优选地,所述疾病选自代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物引起的肝病、酒精引起的肝病、传染因子引起的肝病、炎性肝病、免疫系统功能障碍介导的肝病、血脂异常、心血管疾病、再狭窄、X综合征、代谢综合征、糖尿病、肥胖症、高血压、慢性胆管病变例如原发性硬化性胆管炎(PSC)、原发性胆汁性胆管炎(PBC)、胆道闭锁、3型进行性家族性肝内胆汁淤积症(PFIC3)、炎性肠病、克罗恩病、溃疡性结肠炎、肝癌、肝细胞癌、胃肠癌、胃癌、结肠直肠癌、代谢疾病引起的肝纤维化或硬化、NAFLD引起的纤维化或硬化、NASH引起的纤维化或硬化、酒精引起的肝纤维化或硬化、药物引起的肝纤维化或硬化、传染因子引起的肝纤维化或硬化、寄生虫感染引起的肝纤维化或硬化、细菌感染引起的肝纤维化或硬化、病毒感染引起的纤维化或硬化、HBV感染引起的肝纤维化或硬化、HCV感染引起的肝纤维化或硬化、HIV感染引起的肝纤维化或硬化、HCV和HIV双重感染引起的肝纤维化或硬化、放疗或化疗引起的纤维化或硬化、胆道纤维化、由任何慢性胆汁淤积性疾病造成的肝纤维化或硬化、任何病因的消化道纤维化、克罗恩病引起的纤维化、溃疡性结肠炎引起的纤维化、肠(例如小肠)纤维化、结肠纤维化、胃纤维化、肺纤维化、慢性炎性气道疾病例如COPD、哮喘、肺气肿、吸烟者的肺、肺结核继发的肺纤维化、肺纤维化、特发性肺纤维化(IPF)。
术语“治疗”是指在需要的对象中障碍的治愈或预防。治疗包括向具有宣称的障碍的对象即患者施用化合物、特别是包含在药物组合物中的所述化合物,以治愈、延迟、逆转或减缓所述障碍的发展,由此改善所述患者的状况。治疗也可以施用给健康或处于发生胆汁淤积或纤维化障碍的风险中的对象,以预防或延迟所述障碍。
因此,根据本发明,免疫、炎性、代谢、纤维化和胆汁淤积性疾病的治疗,包括向具有宣称的障碍的对象施用本发明的组合,例如以含有所述组合的组分(i)和(ii)的药物组合物的形式,以治愈、延迟、逆转或减缓所述障碍的发展,由此改善所述患者的状况,或施用给健康对象,特别是处于发生这些疾病的风险中的对象。
所述治疗包括将本发明的组合施用给具有宣称的障碍的患者,以治愈、延迟或减缓所述发展,由此改善所述患者的状况,或施用给健康对象,特别是处于发生炎性、代谢、纤维化和胆汁淤积性疾病的风险中的对象。
所述待治疗的对象是哺乳动物,优选为人类。根据本发明,所述待治疗的对象可以基于与纤维化疾病相关的几种判据例如以前的药物治疗、伴随的疾病、基因型、向风险因子的暴露、病毒感染的基础上,以及在可以利用成像方法和免疫学、生物化学、酶学、化学或核酸检测方法评估的任何相关生物标志物的检测的基础上选择。
根据本发明,所述待治疗的对象可以在与炎性、代谢、纤维化和胆汁淤积性疾病相关的几种判据例如以前的药物治疗、伴随的疾病、基因型、向风险因子的暴露、病毒感染的基础上,以及在可以利用成像方法和免疫学、生物化学、酶学、化学或核酸检测方法评估的任何其他相关生物标志物的基础上选择。
在特定实施方式中,炎性、代谢、纤维化和胆汁淤积性疾病的治疗可以包括施用包含至少两种式(I)的化合物的组合物。在这个实施方式中,所述被施用的组分(ii)与所述至少两种式(I)的化合物被提供在相同组合物中,或以分开的形式例如在不同组合物中。
在另一个实施方式中,本发明的组合用于在疗法中同时、顺序或分开施用,因此可能被包括在不同组合物中。在顺序施用的情况下,所述式(I)的化合物、特别是ELA,可以在组分(ii)之前施用,或者组分(ii)在所述式(I)的化合物之前施用。
式(I)的化合物可以被配制成可药用盐,特别是与制药应用相容的酸或碱盐。式(I)的化合物的盐包括可药用酸加成盐、可药用碱加成盐、可药用金属盐、铵盐和烷基化铵盐。这些盐可以在所述化合物的最终纯化步骤期间或通过将所述盐并入到以前纯化的化合物中来获得。
本发明的药物组合物还可以包含在制药背景中可接受的一种或多种赋形剂或介质(例如盐水溶液、生理溶液、等渗溶液等,其与制药用途相容并且本领域普通技术人员公知)。
这些组合物还可以包含选自分散剂、增溶剂、稳定剂、防腐剂等的一种或几种试剂或介质。可用于这些剂型(液体和/或注射用和/或固体剂型)的试剂或介质具体来说是甲基纤维素、羟甲基纤维素、羧甲基纤维素、聚山梨酸酯80、甘露糖醇、明胶、乳糖、植物油、阿拉伯树胶、脂质体等。
这些组合物可以被配制成注射用悬液、凝胶、油、软膏、丸剂、片剂、栓剂、粉剂、软胶囊、胶囊、气溶胶等的形式,最终利用盖伦形式或装置以确保延长和/或缓慢释放。对于这种制剂来说,可以有利地使用试剂例如纤维素、碳酸盐或淀粉。
本发明的包含式(I)的化合物和一种或多种组分(ii)的药物组合物可以通过不同途径并以不同形式施用。例如,所述化合物可以通过系统方式、经口、肠胃外、通过吸入、通过鼻喷雾、通过滴鼻或通过注射例如静脉内、通过肌肉内途径、通过皮下途径、通过透皮途径、通过局部途径、通过动脉内途径等施用。
当然,所述施用途径将按照本领域技术人员公知的程序进行改变,以适应于待施用的化合物的形式。
本发明的组合产品的组分(i)和(ii)以治疗有效量施用。在本发明的情形中,术语“有效量”是指所述化合物的足以产生所需治疗结果的量。
相对于所述施用的频率和/或剂量,可以由本领域普通技术人员根据患者、病情、施用形式等改变。通常,对于纤维化疾病的治疗来说,本发明的组合(例如采取药物组合物或套装药剂盒的形式)可以以包括0.01mg/天至4000mg/天例如50mg/天至2000mg/天、特别是100mg/天至1000mg/天之间的组分(i)或组分(ii)的剂量施用。
在本发明的优选实施方式中,ELA与对于伊拉非诺来说剂量在80至120mg/天之间的组分(ii)相组合使用。
在另一个优选实施方式中,所述活性成分以旨在口服摄入的丸剂或片剂的形式,作为一种或多种药物组合物施用。
如有必要,施用可以每日或甚至每日几次进行。
本发明将参考下述非限制性实例进一步描述。
附图说明
在图、表格和文本中使用的缩略语:
α-SMA α-平滑肌肌动蛋白
AP-1 激活蛋白1
ASBTi 顶膜钠互相依赖性胆汁酸转运蛋白抑制剂
ASK1 凋亡信号调控激酶1
AT1 血管紧张肽II受体1型
CLA 共轭亚油酸
COPD 慢性阻塞性肺病
CTGF 结缔组织生长因子
CVC 塞尼克罗克
DGAT 二酰基甘油-O-酰基转移酶
DMSO 二甲基亚砜
DPP4 二肽基肽酶4
ELISA 酶联免疫测定法
EOB 超过预期极值
EOBHSA 超过最高单一因子的预期极值
FABAC 脂肪酸胆汁酸缀合物
FBS 胎牛血清
FGF 成纤维细胞生长因子
FXR 法尼酯X受体
GDF 生长分化因子
GLP-1 胰高血糖素样肽-1
GPCR G蛋白偶联受体
HBV 乙肝病毒
HCV 丙肝病毒
15-HEPE 5-羟基二十碳五烯酸
HIV 人免疫缺陷病毒
HSC 肝星状细胞
IC50 半最高抑制浓度
iNOS 诱导型一氧化氮合酶
IPF 特发性肺纤维化
LO 脂氧合酶
LPS 脂多糖
LT 白三烯
MAPK 有丝分裂原激活蛋白激酶
MMP-9 基质金属蛋白酶9
MMPase 基质金属蛋白酶
NADPH 烟酰胺腺嘌呤二核苷酸磷酸
NAFLD 非酒精性脂肪性肝病
NASH 非酒精性脂肪性肝炎
NF-κB 核因子-κB
NOX NADPH氧化酶
NSAIDs 非甾类消炎药
PAR 蛋白酶活化的受体
PBC 原发性胆汁性胆管炎
PBS 磷酸盐缓冲盐水
PDE 磷酸二酯酶
PDGF 血小板衍生生长因子
PFIC3 3型进行性家族性肝内胆汁淤积症
PFOR 丙酮酸:铁氧还蛋白氧化还原酶
PPAR 过氧化物酶体增殖物活化受体
PPRE PPAR响应元件
PSC 原发性硬化性胆管炎
ROCK Rho相关蛋白激酶
RTK 受体酪氨酸激酶
SGLT 钠-葡萄糖转运蛋白
STAT 信号转导物和转录活化剂
TGFβ 转化生长因子β
TGFBRI TGFβ受体I型
TGFBRII TGFβ受体II型
THBS1 血小板反应蛋白1
THRβ 甲状腺激素受体β
TIMP 金属蛋白酶1的组织抑制剂
TLR-4 Toll样受体4
VAP-1 血管黏附蛋白-1
VDR 维生素D受体
图1:1mg/kg/天的ELA和10mg/kg/天的OCA的组合对纤维化表面的测量的影响。
图2:3mg/kg/天的ELA和10mg/kg/天的OCA的组合对纤维化表面的测量的影响。
图3:1mg/kg/天的ELA和10mg/kg/天的OCA的组合对肝胶原的影响。
图4:3mg/kg/天的ELA和10mg/kg/天的OCA的组合对肝胶原的影响。
图5:3mg/kg/天的ELA和10mg/kg/天的OCA的组合对纤维化标志物的影响。
图6:在TGFb引起的hHSC中伊拉非诺相比于塞尼克罗克和苯扎贝特的差异抗纤维
化效果
将血清剥夺的HSC与伊拉非诺(A)、塞尼克罗克(B)或苯扎贝特(PPAR panα/γ/δ)预温育1小时,然后用促纤维化细胞因子TGFβ1(1ng/ml)活化。
在温育48小时后,通过ELISA测量α-SMA的表达。
将得到的值转换成与TGFβ1对照相比的抑制百分率。数据被呈现为平均值(三份平行样)±标准偏差(SD)。统计分析通过单向ANOVA然后是Bonferroni事后检验,使用SigmaPlot 11.0软件来进行。[*:p<0.05;**:p<0.01;***:p<0.001(与TGFβ11ng/mL组相比)]。曲线拟合和半数最高抑制浓度(IC50)的计算使用XLFit软件5.3.1.3来进行。
图7:在TGFβ1诱导的hHSC中伊拉非诺与塞尼克罗克的组合协同抑制α-SMA
组合以剂量响应矩阵格式进行检测并按照超过预期极值(EOB)累加模型进行分析。
制备伊拉非诺(行)和塞尼克罗克(列)、包括它们相应的DMSO对照的连续稀释液。
将得到的混合物添加到血清剥夺的HSC,1小时后使用促纤维化细胞因子TGFβ1(1ng/ml)活化。
(A)对于所有组合对来说,与TGFβ1对照相比α-SMA抑制的百分率。数据被呈现为四份平行样的平均值。
(B)EOB评分如材料和方法中所述来计算。EOB值>10的任何化合物对被认为是协同的(颜色从浅灰色到黑色)。也计算了包括所有组合的总EOB评分。
(C)将源自于协同组合对的数据值以条形图表示法作图。数据被呈现为平均值(四份平行样)±标准偏差(SD)。统计分析通过单向ANOVA然后是Bonferroni事后检验,使用Sigma Plot 11.0软件来进行。[*:p<0.05;**:p<0.01;***:p<0.001(与“产品组合”组的比较)]。
图8:在TGFβ1诱导的hHSC中苯扎贝特不与塞尼克罗克协同以减少纤维化
组合以剂量响应矩阵格式进行检测并按照超过预期极值累加模型进行分析。
制备苯扎贝特(行)和塞尼克罗克(列)、包括它们相应的DMSO对照的连续稀释液。将得到的混合物添加到血清剥夺的HSC,1小时后使用促纤维化细胞因子TGFβ1(1ng/ml)活化。
(A)与TGFβ1对照相比α-SMA抑制的百分率。
(B)超过预期极值(EOB)评分如材料和方法中所述来计算。EOB值>10的任何化合物对被认为是协同的(颜色从浅灰色到黑色)。也计算了包括所有组合的总EOB评分。
图9:在TGFβ1诱导的hHSC中伊拉非诺与MSDC-0602、PXS-4728A、阿帕拉酮、CF-102、
维莫德吉、PBI-4050、KD-025、DUR-928、VK-2809和恩利卡生的组合协同抑制α-SMA
组合以剂量响应矩阵格式进行检测并按照超过预期极值(EOB)累加模型进行分析。对于代表性的协同组合来说,将与TGFβ1对照相比α-SMA抑制的百分率以条形图表示法作图。数据被呈现为平均值(四份平行样)±标准偏差(SD)。*:p<0.05;;**:p<0.01;***:p<0.001,使用单向ANOVA和Fisher的最小显著差(LSD)事后检验。MSDC=MSDC-0602。
图10:在肝微量组织中伊拉非诺与CP-640186、GS-0976或JKB-121(纳美芬)的组合
协同抑制胶原生产
将微量组织用含有或不含单独的伊拉非诺(白色条)、单独的化合物(ii)(黑色条) 或两者的组合(灰色条)的NASH刺激物的代谢诱导进行处理。组合以剂量响应矩阵格式进行检测并按照超过预期极值(EOB)累加模型进行分析。对于代表性的协同组合来说,将与NASH刺激物对照相比的抑制百分率以条形图表示法作图。数据被呈现为平均值(三份平行样)±标准偏差(SD)。*:p<0.05;**:p<0.01;***:p<0.001,使用单向ANOVA和Fisher的最小显著差(LSD)事后检验。
图11:在LPS活化的巨噬细胞中伊拉非诺与吉卡宾的组合协同抑制TNFα分泌。
组合以剂量响应矩阵格式进行检测并按照超过预期极值(EOB)累加模型进行分析。对于代表性的协同组合来说,将与LPS对照相比TNFα分泌的抑制百分率以条形图表示法作图。数据被呈现为平均值(四份平行样)±标准偏差(SD)。*:p<0.05;**:p<0.01;***:p<0.001,使用单向ANOVA和Fisher的最小显著差(LSD)事后检验。
图12:在HepG2中伊拉非诺与CP640186、VK-2809、阿帕拉酮(Apa)或阿拉乔尔
(Aram)的组合协同抑制脂肪积累。
组合以剂量响应矩阵格式进行检测并按照超过预期极值(EOB)累加模型进行分析。对于代表性的协同组合来说,将与FFA处理的对照相比脂肪积累的抑制百分率以条形图表示法作图。数据被呈现为平均值(四份平行样)±标准偏差(SD)。*:p<0.05;**:p<0.01;***:p<0.001,使用单向ANOVA和Fisher的最小显著差(LSD)事后检验。
图13:在3D Huh7球状体培养物中伊拉非诺与MGL-3196的组合协同抑制脂肪积累。
将球状体用含有或不含单独的伊拉非诺(白色条)、单独的MGL3196(灰色条)或两
者的组合(黑色条)的代谢NASH刺激物进行处理。脂类积累的测量如材料和方法中所述进
行。标准偏差被显示为误差条(n=3)。计算的EOB值陈述在左上方。在单向方差分析(ANOVA)
和Fisher的最小显著差(LSD)检验后的显著差异(*p<0,05;**p<0,01***;p<0,001)。
图14:在具有NASH的小鼠(CDFF喂食的小鼠)中伊拉非诺(GFT505,3mg/kg/天)和塞
隆塞比(SEL,30mg/kg/天)协同作用以减少纤维化、组织重塑和炎性标志物。
(A)通过天狼猩红阳性区域相对于肝切片区域的形态测量定量,评估纤维化表面的百分率。
(B)肝胶原含量。
(C)血浆PIIINP浓度,其是肝纤维化的替代标记物。
(D)血浆TIMP1浓度,其是肝纤维化的替代标记物。
作为纤维化和组织重塑的标志物的Col1α1(E)、MMP2(F)、TGFβ1(G)和作为炎症标志物的TNFα(H)和CCR2(I)的表达,通过实时定量PCR进行评估。
数据被表示为平均值±SD。¤p<0.05,¤¤p<0.01,¤¤¤p<0.001,使用单侧Student t-检验和Welsh校正。HAS,最高单因子模型。
图15:在具有NASH的小鼠(CDFF喂食的小鼠)中伊拉非诺(GFT505,1或3mg/kg/天)
和GKT-831(GKT,60mg/kg/天)协同作用以减少NASH和纤维化。
(A)通过天狼猩红阳性区域相对于肝切片区域的形态测量定量,评估纤维化表面的百分率。
(B)10个显微镜视野区域(20X)中炎性病灶的组织学评估。
(C)NAFLD活性评分,通过按照NASH临床研究网络(Kleiner2005,Brunt 1999)计算脂肪变性、鼓胀和叶炎性等级的总和(最低0–最高8)来评估。
数据被表示为平均值±SD。¤p<0.05,¤¤p<0.01,¤¤¤p<0.001,使用单侧Student t-检验和Welsh校正。$p<0.05,$$p<0.01,$$$p<0.001,使用单侧Mann-Whitney U(非参数)检验。HSA,最高单因子模型。
图16:在具有NASH的小鼠(CDFF喂食的小鼠)中伊拉非诺(GFT505,1mg/kg/天)和
GS-0976(GS,30mg/kg/天)协同作用以减少脂肪变性和体重。
(A)脂肪变性等级,通过按照NASH临床研究网络指南进行组织学检查来评估。
(B)肝甘油三酯含量。
(C)在治疗8周后与对照相比的体重减轻。
数据被表示为平均值±SD。¤p<0.05,¤¤p<0.01,¤¤¤p<0.001,使用单侧Student t-检验和Welsh校正。HSA,最高单因子模型。
具体实施方式
实施例
实施例1:组合疗法研究设计
材料和方法
化合物被溶解在二甲基亚砜(DMSO,Fluka cat#41640)中。
1.TGFβ1诱导的hHSC的模型的说明
hHSC培养
将人类原代肝星状细胞(hHSC)(Innoprot)在增补有2%胎牛血清(FBS,ScienCellcat#0010)、1%青霉素/链霉素(ScienCell cat#0503)和星状细胞生长增补物(SteCGS;ScienCell cat#5352)的STeCM培养基(ScienCell cat#5301)中培养。细胞培养瓶用聚L-赖氨酸(Sigma cat#P4707)包被用于更好地粘附。
组合物的制备
2组分组合矩阵
对于这些实验来说,产生了棋盘矩阵。将ELA和组分(ii)储用液以96孔板的行中5个点的系列(ELA)和列中11个点的系列(组分(ii))在DMSO中连续稀释。随后,通过将所有单一药剂浓度1:1混合,产生5X11组合矩阵。每种化合物的测试浓度基于作为单一药剂的每种化合物的相应的IC50进行选择,所述IC50通过在用TGF-β1刺激的HSC模型中测量α-SMA含量来获得。
使用TGF-β1活化hHSC和化合物处理
将人类原代肝星状细胞(hHSC)(Innoprot)如上所述在标准条件下培养。然后将所述细胞以2x 104个细胞/孔的密度铺于96孔板中,用于通过ELISA测量α-SMA。第二天除去细胞培养基,并将细胞用PBS(Invitrogen cat#14190)清洗。将hHSC在无血清和无SteCGS培养基中剥夺24小时。对于使用ELA、组分(ii)和相应的ELA/组分(ii)组合的处理来说,将所述血清剥夺的hHSC与化合物预温育1小时,然后在无血清和无SteCGS培养基中添加促纤维化刺激物TGF-β1(PeproTech cat#100-21,1ng/mL),另外温育48小时的时间段。
α-SMA ELISA
α-SMA的水平使用夹心ELISA来测量。简单来说,将ELISA板的孔首先用捕获抗体(小鼠抗ACTA2单克隆抗体,Abnova)在4℃包被过夜。在PBS+0.2%Tween 20中清洗三次后,添加由PBS+0.2%BSA组成的阻断溶液1小时,然后进行另一个清洗循环。将细胞裂解物转移到孔中,用于在室温下结合到所述捕获抗体为期2h。在清洗程序后,添加检测抗体(生物素化的小鼠抗ACTA2单克隆抗体,Abnova),在室温下2小时,然后进行3次清洗。为了检测,首先施加HRP偶联的链亲合素(R&D Systems cat#DY998),在室温下30min。在清洗后,添加HRP底物TMB(BD,#555214),并在暗处在室温温育7min。在氧化后,TMB形成水溶性蓝色反应产物,其在添加硫酸(溶液终止)后变成黄色,能够使用分光光度计在450nm处准确测量强度。产生的颜色与裂解物中存在的α-SMA的量直接成比例。
2.3D人类肝微量组织中HSC活化的模型的说明
3D人类肝微量组织培养
冷冻保存的原代人类肝细胞(IPHH_11)和冷冻保存的原代人类非实质细胞(NPC,IPHN_11)从Bioreclamation IVT获得。冷冻保存的人类原代肝星状细胞(hHSC)从Innoprot获得。3D InSightTM人类肝微量组织(MT-02-302-95;InSphero AG)使用IPHH_11、IPHN_11和hHSC,在96孔悬滴培养平台(Gravity PLUSTM)中生产。在微量组织形成后,它们被转移到微量组织特异性96孔培养和测定平台(Gravity TRAPTM)。进一步的维持和化合物处理在Gravity TRAPTM板中进行。在组织形成后,将所述3D微量组织在37℃下,在加湿的5%CO2细胞培养箱中,在3D InSightTM人类肝维持培养基-INF(hLiMM CS-07-001b-01;InSphero AG)中维持4天。每2天更新一半的培养基。组合物的制备:2组分组合矩阵
对于这些实验来说,产生了棋盘矩阵。将ELA和组分(ii)储用液以96孔板的行中2个点的系列(ELA)和列中3个点的系列(组分(ii))在DMSO中连续稀释。随后,通过将所有单一药剂浓度1:1混合,产生2X3组合矩阵。
3D InSightTM人类肝微量组织的代谢刺激和化合物处理
3D InSightTM人类肝微量组织(InSPhero)如上所述在标准条件下培养。然后将微量组织在无血清培养基中剥夺24小时。对于使用ELA、组分(ii)和相应的ELA/组分(ii)组合的处理来说,将所述血清剥夺的微量组织用NASH刺激物和化合物两者的代谢诱导进行处理(第0天),然后在第3天更新NASH刺激物的代谢诱导另外3天的时间段。在第6天收获用于Col1α1测量的上清液。
Col1α1 ELISA
Col1α1的水平使用夹心ELISA来测量。简单来说,将ELISA板的孔首先用捕获抗体(小鼠抗人类前胶原Iα1捕获抗体,“Elisa前胶原Iα1/COLIA1”,DuoSet ELISA,R&D,目录号DY6220-05)在RT包被过夜。在PBS+0.05%Tween 20中清洗三次后,添加由PBS+1%BSA组成的阻断溶液1小时,然后进行另一个清洗循环。将细胞上清液转移到孔中,用于在室温下结合到所述捕获抗体为期2h。在清洗程序后,添加检测抗体(生物素化的绵羊抗人类前胶原Iα1检测抗体),在室温下2小时,然后进行3次清洗。为了检测,首先施加HRP偶联的链亲合素,在室温下20min。在清洗后,添加HRP底物TMB(BD,#555214),并在暗处在室温温育20min。在氧化后,TMB形成水溶性蓝色反应产物,其在添加硫酸(溶液终止)后变成黄色,能够使用分光光度计在450nm处准确测量强度。产生的颜色与上清液中存在的col1α1的量直接成比例。
3.LPS活化的巨噬细胞的说明
THP-1单核细胞分化成巨噬细胞
将THP-1单核细胞(ECACC#88081201)以每个孔25550个细胞的密度接种在384孔板中增补有10%SVF的RPMI1640(Gibco,21875)中,并使用终浓度为100ng/ml的PMA(佛波醇12-肉豆蔻酸酯13-乙酸酯,Sigma,P8139)24小时,分化成巨噬细胞。
组合物的制备:2组分组合矩阵
对于这些实验来说,产生了棋盘矩阵。将ELA和组分储用液以96孔板的行中6个点的系列(ELA)和列中10个点的系列(组分)在DMSO中连续稀释。随后,通过将所有单一药剂浓度1:1混合,产生6X10组合矩阵。
化合物处理和LPS刺激
在使用PMA 24小时后,除去培养基并用无血清RPMI替换。对于使用ELA、组分和相应的ELA/组分组合的处理来说,将所述血清剥夺的THP-1巨噬细胞与所述化合物预温育24小时,然后添加脂多糖LPS(100ng/ml,E.coli 055B5,Sigma,L6529)另外6小时的时间段。
人类TNFα定量
在FRET技术的基础上,使用均相时间分辨荧光(HTRF)技术(Cisbio 62HTNFAPEG)定量上清液中的人类TNFα。FRET(荧光共振能量转移)是基于两个荧光团即供体和受体之间在邻近时的能量转移。生物分子之间的分子相互作用,可以通过将具有荧光标记物的每种配偶体偶联并检测能量转移的水平(665nm)来评估。将细胞上清液、样品或标准品直接分发到测定板中,用于通过试剂进行检测。将用HTRF供体和受体标记的抗体预先混合并添加到单个分发步骤中。信号强度与形成的抗原-抗体复合物的数目并因此与TNFα浓度成正比。通过用4参数逻辑模型拟合数据,获得7个点的标准曲线(供应的人类TNFα从39pg/ml至2500pg/ml)。
4.载有脂肪的肝细胞(HepG2)的说明
HepG2培养
将人类肝细胞癌在增补有10%胎牛血清(FBS,Gibco cat#10270)、1%青霉素/链霉素(Gibco cat#15140)、1%MEM NEAA(Gibco cat#11140)、1%L-谷氨酰胺(Gibco cat#25030)和1%丙酮酸钠(Gibco cat#11360)的DMEM 4.5g/L葡萄糖(Gibco cat#31053)中培养。
组合物的制备:2组分组合矩阵
对于这些实验来说,产生了棋盘矩阵。将ELA和组分储用液以384孔板的行中5个点的系列(ELA)和列中11个点的系列(组分)在DMSO中连续稀释。随后,通过将所有单一药剂浓度1:1混合,产生5X11组合矩阵。
游离脂肪酸(FFA)制备
油酸(#O1383)和棕榈酸(P0500)在Sigma购买。FFA储用溶液(100mM)在0.1M NaOH中在80℃下制备。通过将适合体积的储用溶液在55℃水浴中(15min)络合到10%BSA(无FFA,低内毒素;Sigma-Aldrich,Bornem,Belgium),制备4.5mM棕榈酸/10%牛血清白蛋白(BSA)和9mM油酸/10%BSA的工作溶液。
脂肪装载和化合物处理
将HepG2以40000个细胞/孔的密度铺板在384孔板中,以评估脂类小滴含量。第二天,除去细胞培养基,将细胞用PBS(Invitrogen cat#14190)清洗。将HepG2在无血清培养基中剥夺24小时。对于使用ELA、组分和相应的ELA/组分组合的处理来说,将所述血清剥夺的HepG2与所述化合物预温育24小时,然后添加终浓度为0.5mM的油酸:棕榈酸混合物(2:1)另外24小时的时间段。
细胞内脂类小滴测量
为了测量细胞内脂类小滴含量,将所述细胞带到室温并用40μL PBS清洗。将细胞与40μL稀释的Adipored试剂(2.5μL Adipored试剂每200μL PBS)(Lonza,Walkersville,MD)在室温温育30min。使用荧光光度计(Spark Tecan cat#30086376SN#1801002745)测量相对荧光(k激发在485nm处,k发射在580nm处)。在四份平行样中进行分析。
5.3D Huh7球状体培养物的说明
3D Huh7球状体培养
冷冻保存的Huh7购自ECACC。细胞在ULA板(Costar)中,在含有10%FBS(Gibco)的William’s培养基(Sigma)中,在37℃下在加湿的5%CO2细胞培养箱中生长。细胞在5天内聚集并形成球状体。
组合物的制备:2组分组合矩阵
对于这些实验来说,产生了棋盘矩阵。将ELA和组分(ii)储用液以96孔板的行中2个点的系列(ELA)和列中3个点的系列(组分(ii))在DMSO中连续稀释。随后,通过将所有单一药剂浓度1:1混合,产生2X3组合矩阵。
3D Huh7球状体培养物的代谢刺激和化合物处理
3D Huh7球状体如上所述在标准条件下培养。然后将它们在无血清培养基中剥夺24小时。对于使用ELA、组分(ii)和相应的ELA/组分(ii)组合的处理来说,将所述血清剥夺的球状体用代谢NASH刺激物和所述化合物两者处理(第0天),然后在第4天更新所述代谢NASH刺激物和化合物另外3天的时间段。在第7天将所述球状体染色用于脂类积累。
脂类染色和定量
细胞内脂类积累使用AdipoRedTM测定试剂(Lonza)来定量。使用荧光读板器(TECAN),在λexc:485nm和λem:572nm处对球状体进行荧光测定法定量。
结果和讨论
分化的肌成纤维细胞的异常的持久性是许多纤维化疾病的特征。在肝损伤后,沉寂的HSC经历以分化成(α-SMA)阳性肌成纤维细胞为特征的活化过程。PPAR激动剂伊拉非诺在用促纤维化细胞因子TGFβ1活化的hHSC中具有抗纤维化活性(图9)。在本文中令人吃惊地显示,MSDC-0602、PXS-4728、阿帕拉酮、CF-102(纳莫德森)、维莫德吉、PBI-4050、恩利卡生、DUR-928、VK-2809或KD-025与伊拉非诺的组合协同抑制HSC的α-SMA生产(图9)。
由于肝脏由不同的细胞类型(肝细胞、免疫细胞、HSC……)构成,并且由于HSC活化可以从涉及其他肝细胞的不同刺激物产生,因此肝微量组织模型也被用于测试对纤维化的组合治疗。使用代谢NASH刺激物的处理增加了微量组织的胶原生产。在这个模型中,伊拉非诺与CP-640186、GS-0976和纳美芬协同作用以抑制胶原生产(图10)。
合在一起,这些结果显示出伊拉非诺与MSDC-0602、PXS-4728、阿帕拉酮、CF-102(纳莫德森)、维莫德吉、PBI-4050、恩利卡生、DUR-928、VK-2809、KD-025、CP-640186、GS-0976或纳美芬(JKB-121)的组合的协同抗纤维化效果。
代谢疾病例如NAFLD/NASH与低等级炎症相关。免疫细胞的活化产生改变肝脏和周围器官(脂肪组织、胰腺……)的代谢功能的细胞因子。在代谢和肝病中描述的肠通透性,导致循环细菌组分(脂多糖或LPS)的增加,其活化肝和周围器官(脂肪组织)中的巨噬细胞。由于PPAR具有抗炎活性,因此我们调查了伊拉非诺和其他化合物是否可以抑制巨噬细胞被LPS的激活。在分化成巨噬细胞的THP1单核细胞的模型中,LPS处理激活巨噬细胞,正如通过TNFα分泌所测量的。单独的伊拉非诺(1μM)将TNFα抑制21%(图11)。令人吃惊的是,伊拉非诺与吉卡宾的组合将TNFα分泌强烈抑制50%(图11)。因此,这个结果显示出伊拉非诺与其他化合物协同作用以减轻在包括NASH和代谢疾病的大量疾病中观察到的炎性状况的能力。
NAFLD/NASH以肝细胞中的原发性脂肪积累(脂肪变性)为特征,其诱导脂毒性,引起炎症、细胞死亡、组织重塑并最终引起纤维化。由于PPARα和PPARδ已知诱导脂肪氧化并抑制脂质新生,因此我们想看看与其他化合物组合的伊拉非诺是否能够在肝细胞中阻止脂肪积累。因此,将HepG2细胞用游离脂肪酸(FFA)处理以诱导脂类小滴的积累。在这个模型中,单独的伊拉非诺(10μM)将脂肪积累减少20%。出人意料的是,当将伊拉非诺与CP-640186、VK-2809、阿帕拉酮或阿拉乔尔组合时,所述减少达到40%(图12)。
也使用肝细胞的三维(3D)体外模型来应对这个问题,其允许更加生理性地再生肝脏的结构体系。在这个模型中,通过用代谢NASH刺激物处理获得了脂肪积累。伊拉非诺(3μM)将脂肪含量减少12%(图13)。伊拉非诺与MGL-3196(1μM)的组合将肝细胞脂类含量强烈减少28%(图13),当两种药物一起使用时显示出协同效应。
合在一起,这些结果显示出伊拉非诺与CP-640186、VK-2809、阿帕拉酮、阿拉乔尔和MGL-3196协同作用,以特别是减少脂肪变性。
总而言之,这些结果显示了伊拉非诺与MSDC-0602、PXS-4728、阿帕拉酮、CF-102(纳莫德森)、维莫德吉、PBI-4050、恩利卡生、DUR-928、KD-025、CP-640186、GS-0976、纳美芬(JKB-121)、VK-2809、MGL-3196和阿拉乔尔协同作用,以特别是减轻NAFLD的能力。
实施例2:ELA与OCA的组合
材料和方法
在长期CDAA+1%胆甾醇模型(12周)中伊拉非诺、OCA和伊拉非诺+OCA组合的评估
在喂食CDAA+1%胆甾醇饮食的大鼠的纤维化NASH模型中评估单独的伊拉非诺、单独的OCA和两者的组合的预防效果。将150-175g雄性Wistar大鼠喂食对照(CSAA)饮食、CDAA+1%胆甾醇饮食或增补有伊拉非诺1、3和10mg/kg/天、OCA 10和30mg/kg/天或组合药物(伊拉非诺1、3和10mg/kg/天与OCA 10mg/kg/天相组合)的CDAA+1%胆甾醇饮食12周。
每周两次监测体重和食物摄入量。在治疗的最后一天,将大鼠在6h禁食期后处死。快速剖出肝脏用于生物化学和组织学研究。
所有动物程序按照标准流程并根据实验室动物的适当护理和使用的标准推荐来进行。
组织学
组织包埋和制片:
首先将肝薄片在4%福尔马林溶液中固定12小时。然后,将肝块在PBS中清洗30分钟,并在乙醇溶液(70、80、95和100%乙醇的连续浴)中脱水。将所述肝块在三种不同的二甲苯(Sigma-Aldrich cat#534056)浴中温育,然后在两个液体石蜡浴中温育(56℃)。然后将肝块置于样品架中,轻柔地填充以完全覆盖所述组织。
将含有组织块的石蜡块从样品架取出并储存在室温。将肝块切成3μm薄片。
苏木精/曙红染色
将肝切片脱石蜡化、重新水化并在Mayer’s苏木精(Microm,cat#F/C0303)中温育3分钟。然后,将所述肝切片在水中漂洗并在曙红G(VWR,cat#1.09844.1000)中温育1分钟。将切片在水中漂洗,然后脱水,并使用CV封片介质(Leica,cat#14046430011)封片。
天狼猩红染色
将肝切片脱石蜡化、重新水化并在固绿FCF 0.1%(Sigma-Aldrich,cat#F7258)溶液中温育15分钟,然后在0.5%乙酸(Panreac,cat#131008.1611)浴中漂洗。然后,将所述肝切片在水中漂洗,并在0.1%天狼猩红(Direct Red 80,Fluka cat#43665)在饱和水性苦味酸(Sigma-Aldrich cat#P6744)中的溶液中温育30分钟。然后将切片脱水,并使用CV封片介质(Leica,cat#14046430011)封片。
组织学检查
对每个肝样本的来源不知情的技术员进行组织学检查。使用来自于3D Histech的Pannoramic 250扫描仪产生虚拟切片。对于每只动物,按照NASH临床研究网络(Kleiner2005,Brunt 1999)赋予概述了NASH的主要组织学病变的评分。简单来说,对脂肪变性,叶炎症和肝细胞鼓胀进行评分。为每个个体确立作为脂肪变性(0-3)、叶炎症(0-3)和鼓胀(0-2)损伤分级的未加权总和的NAFLD活动性评分(NAS评分)。
使用Quant Center软件(3D Histech,包括Pattern Quant和Histo Quant模块),对染色的胶原区域进行定量。简单来说,Pattern Quant被用于检测所述组织并测量它的表面。然后,将Histo Quant用于检测染色的胶原含量并在颜色阈值方法的基础上测量它的表面。然后将纤维化面积表示为每只动物的胶原表面占全部组织的百分率。
肝胶原含量的测量
肝胶原含量使用适合的QuickZyme试剂盒(总胶原测定法,cat#QZB-totcol2)来确定。所述测定法是基于羟脯氨酸的检测,这是一种主要存在于胶原三螺旋中的非蛋白质氨基酸。因此,组织水解物中的羟脯氨酸可用作组织中存在的胶原的量的直接度量(不区分前胶原、成熟胶原和胶原降解产物)。
在定量羟脯氨酸之前,需要将组织样品在6M HCl中在95℃下完全水解。所述测定法导致在570nm处具有最大吸收的发色体的产生。结果被表示为mg胶原/g肝脏。
α2巨球蛋白(α2M)
α2M的血浆浓度使用Abcam试剂盒(cat#ab157730),按照制造商的说明书来确定。简单来说,将微孔板用特异性针对大鼠α2M的抗体预包被。然后将标准品、对照和样品吸取到孔中,并且血浆中存在的任何α2M被固定化的抗体结合。在清洗后,向所述孔添加辣根过氧化物酶标记的第二抗体。在清洗后,向所述孔添加底物溶液。通过添加终止溶液将所述酶反应终止。在450nm处测量到的颜色的强度与初始步骤中结合的α2M的量成正比。然后从标准曲线推导出样品值。结果以ng/mL为单位表述。
前胶原III N-端前肽(PIIINP)
PIIINP的血浆浓度使用来自于Cloud-Clone Corp的ELISA测定法(cat#SEA573Ra),按照制造商的说明书来确定。将微孔板用特异性针对PIIINP的抗体预包被。将标准品或样品添加到具有特异性针对PIIINP的生物素偶联的抗体的适合的微孔板孔。接下来,向每个微孔板孔添加偶联到辣根过氧化物酶(HRP)的亲和素并温育。在添加TMB底物溶液后,只有那些含有PIIINP、生物素偶联的抗体和酶偶联的亲和素的孔表现出颜色变化。通过添加硫酸溶液终止所述酶-底物反应,并在450nm±10nm的波长处通过分光光度法测量颜色变化。然后通过将样品的OD与标准曲线进行比较来确定样品中PIIINP的浓度。结果以pg/mL为单位表述。
肝基因表达分析
使用RNeasy小型试剂盒(Qiagen),遵照制造商的说明书从大鼠肝分离总RNA。使用M-MLV RT(莫洛尼鼠白血病病毒反转录酶)(Invitrogen cat#28025),在1x RT缓冲液(Invitrogen)、0.5mM DTT(Invitrogen)、0.18mM dNTP(Promega)、200ng pdN6(Amersham)和30U RNase抑制剂(Promega)中,将总RNA反转录成cDNA。
然后使用CFX96 TouchTM实时PCR检测系统(Biorad)进行定量PCR。简单来说,所述PCR反应以96孔板格式,在含有1μL反转录反应产物、0.5μL反向和正向引物(各10pmol)和12,5μl 2X iQ SYBR Green Supermix(BioRad)的25μl总体积中进行,使用了下述引物序列:
使用样品中作为参比看家基因的RPLP0基因的表达,将表达水平归一化。对于每种基因来说,通过选择最佳点(至少三个点)以便具有接近100%的PCR反应效率和接近1的相关系数,来绘制标准曲线。对于所述看家基因和靶基因两者来说,使用所述标准曲线方程确定表达水平(将每种靶基因的特定PCR效率考虑在内)。
结果和讨论
结果报告在下面的表和图1-5中。
与未治疗的CDAA+1%胆甾醇大鼠相比的百分率
**p<0.01,***p<0.001,与CDAA+1%胆甾醇组相比(ANOVA+Bonferroni)
#p<0.05,##p<0.01,与最佳单一药剂相比t(Student t-检验)
(+炎症的标志物)
西方生活方式总是与非酒精性脂肪性肝炎(NASH)这种常常发展成肝纤维化和硬化并可能最终引起肝细胞癌的慢性肝病的高发病率相关。目前没有批准的用于NASH的疗法。同时导向多个治疗靶点的药物组合具有极大提高药物相应并有益于最广泛的患者群体的潜力。药物组合以前在其他系统性疾病例如高血压、血脂异常或2型糖尿病中进行了试验,并显示出更好地控制隐晦的疾病并降低发病率和死亡率。在最近的2B期研究中,伊拉非诺(PPARα/δ激动剂)和OCA(FXR激动剂)两者对NASH和纤维化终点显示出效果。我们想比较它们对相关NASH病理结果的作用并寻找所述组合的治疗益处。
为了实现这个目的,通过用增补有胆甾醇的缺少胆碱的L-氨基酸限定饮食(CDAA/chol饮食)喂食Wistar大鼠,诱导了NASH组织学和纤维化。干预组中的动物在整个研究期间接受伊拉非诺或OCA或两种化合物。NASH和纤维化的发生通过组织学来评估。也对不同的相关生物标志物进行了另外的生物化学和分子分析。
喂食CDAA/chol饮食的Wistar大鼠发生NASH相关的组织学和纤维化以及严重疾病的高度渗透。在所有动物中存在晚期脂肪变性、叶炎症和鼓胀,并且NAS评分在6至8之间不等。对于喂食CDAA/c饮食并且未接受药物治疗的所有动物来说,肝组织学(天狼猩红阳性面积)和生物化学(肝胶原浓度)显示出肝纤维化含量平均提高4倍,并且纤维化评分为3或4。与炎症、氧化胁迫、组织重塑和纤维化相关的基因的表达提高,并与以前在重症NASH患者中报道的基因特征相一致。
伊拉非诺和OCA的单独施用引起纤维化发生的非常显著的减弱。在接受两种化合物的动物中观察到对纤维化的类似效果,尽管剂量明显更低。通过鼓胀判断的肝细胞损伤,被伊拉非诺以剂量依赖性的方式阻止或减弱。相反,OCA在本研究中使用的剂量下仅仅显示出部分的鼓胀减弱。叶炎症被伊拉非诺以剂量依赖性的方式减弱,并且与OCA相比程度更低。最后,任一种药物候选物的单独施用部分减弱了组织重塑、炎症和氧化胁迫标志物的提高,并且两种化合物的组合与任一单一药剂相比更加有效。
因此,本文中显示,在CDAA/c饮食诱导的NASH模型中伊拉非诺和OCA对肝纤维化的协同作用,在与任何单一药剂相比明显更低的两种药物候选物的剂量下产生可比的治疗益处。从本研究可以可信地预期,为了获得与单独使用的每种化合物的初始剂量相近的结果,两种药物候选物的剂量可以被降低至少1.5、2、2.5倍或甚至至少3倍。此外,伊拉非诺对肝损伤显示出明显的保护效果。在这个模型中,OCA对鼓胀和叶炎症的效果相对适度。从本研究可以得出结论,伊拉非诺/OCA组合将有益于更广泛的患者群体,并且相关的治疗剂量降低将减少不利药物作用的发生。
实施例3:ELA与CVC的组合
材料和方法
化合物被溶解在二甲基亚砜(DMSO,Fluka cat#41640)中。CVC从CLINISCIENCES商业化获得(Réf:A13643-10,批号:497223-25-3)。苯扎贝特在Genfit合成。
hHSC培养
将人类原代肝星状细胞(hHSC)(Innoprot)在增补有2%胎牛血清(FBS,ScienCellcat#0010)、1%青霉素/链霉素(ScienCell cat#0503)和星状细胞生长增补物(SteCGS;ScienCell cat#5352)的STeCM培养基(ScienCell cat#5301)中培养。细胞培养瓶用聚L-赖氨酸(Sigma cat#P4707)包被用于更好地粘附。
组合物的制备
2组分组合矩阵
对于这些实验来说,产生了棋盘矩阵。将CVC和伊拉非诺储用液以96孔板的行中5个点的系列(伊拉非诺)和列中6个点的系列(塞尼克罗克)在DMSO中连续稀释。随后,通过将所有单一药剂浓度1:1混合,产生6X7组合矩阵。每种化合物的测试浓度基于作为单一药剂的每种化合物的相应的IC50进行选择,所述IC50通过在用TGF-β1刺激的HSC模型中测量α-SMA含量来获得。
使用TGF-β1活化hHSC和化合物处理
将人类原代肝星状细胞(hHSC)(Innoprot)如上所述在标准条件下培养。然后将所述细胞以2x 104个细胞/孔的密度铺于96孔板中,用于通过ELISA测量α-SMA。
第二天除去细胞培养基,并将细胞用PBS(Invitrogen cat#14190)清洗。将hHSC在无血清和无SteCGS培养基中剥夺24小时。对于使用CVC、伊拉非诺、苯扎贝特和CVC/伊拉非诺和CVC/苯扎贝特的成对组合的处理来说,将所述血清剥夺的hHSC与化合物预温育1小时,然后在无血清和无SteCGS培养基中添加促纤维化刺激物TGF-β1(PeproTech cat#100-21,1ng/mL),另外温育48小时的时间段。
α-SMA ELISA
α-SMA的水平使用夹心ELISA来测量。简单来说,将ELISA板的孔首先用捕获抗体(小鼠抗ACTA2单克隆抗体,Abnova)在4℃包被过夜。在PBS+0.2%Tween 20中清洗三次后,添加由PBS+0.2%BSA构成的阻断溶液1小时,然后进行另一个清洗循环。将细胞裂解物转移到孔中,用于在室温下结合到所述捕获抗体为期2h。在清洗程序后,添加检测抗体(生物素化的小鼠抗ACTA2单克隆抗体,Abnova),在室温下2小时,然后进行3次清洗。为了检测,首先施加HRP偶联的链亲合素(R&D Systems cat#DY998),在室温下30min。在清洗后,添加HRP底物TMB(BD,#555214),并在暗处在室温温育7min。在氧化后,TMB形成水溶性蓝色反应产物,其在添加硫酸(溶液终止)后变成黄色,能够使用分光光度计在450nm处准确测量强度。产生的颜色与裂解物中存在的α-SMA的量直接成比例。
通过超过预期极值(EOB)方法确定协同作用
首先将在α-SMA ELISA测定法中获得的值转变成与TGF-β1对照相比的抑制百分率。然后,使用这些抑制百分率确定EOB(超过预期极值),以定义药物组合的协同效应。首先通过下述方程确定预期极值累加分值(E):
E=(A+B)-(A×B),其中A和B是伊拉非诺(A)(或苯扎贝特)和塞尼克罗克(B)在给定剂量下的抑制百分率。在同一剂量下所述组合的CVC/伊拉非诺(或苯扎贝特)的极值预期值和观察到的抑制之间的差值,是“超过预期极值”分值。
-超过预期极值分值=0表明所述组合治疗是累加的(正如对独立途径效果所预期的);
-超过预期极值分值>0表明高于累加的活性(协同);并且
-超过预期极值分值<0表明所述组合低于累加(拮抗作用)。
对于组合伊拉非诺+CVC和苯扎贝特+CVC来说,通过将所有EOB加和来计算额外的总极值分值。
为了确认协同作用,对于CVC/伊拉非诺组合来说,将对应于最高EOB分值的实验值在条形图上作图。
CVC/伊拉非诺或CVC/苯扎贝特与最高的单一药剂之间观察到的差异的显著性,通过student’s t-检验来确定。[*:p<0.05;**:p<0.01;***:p<0.001]
结果和结论:
分化的肌成纤维细胞的异常的持久性是许多纤维化疾病的特征。
在肝损伤后,沉寂的HSC经历以分化成(α-SMA)阳性肌成纤维细胞为特征的活化过程。
在用促纤维化细胞因子TGFβ1活化的hHSC中PPAR激动剂伊拉非诺揭示出抗纤维化活性。α-SMA标志物降低80%,并且IC50为3,17μM(图6A)。然而,其他PPAR激动剂如苯扎贝特显示出微弱的抗纤维化特性(图6C),表明PPAR激动剂在它们的抗纤维化性能方面并不等同。在TGFβ活化的HSC中,单独的CVC在所有剂量下不显示出显著效果(图6B)。为了评估伊拉非诺与CVC的组合是否能够以协同方式减少纤维化,在TGFβ诱导的HSC中进行了组合矩阵实验。简单来说,将CVC和伊拉非诺溶液以棋盘格式连续稀释,以产生覆盖大量伊拉非诺/CVC比率的42组合矩阵。首先通过计算超过预期极值分值确定协同性。这些实验揭示,在活化的HSC中伊拉非诺可以与CVC协同作用以减少α-SMA生产(图7A和7B)。协同性的最佳实例之一示出在图7C中,其中使用5μM的每种化合物。尽管单独的5μM CVC不显示出任何抗纤维化活性,但它向5μM伊拉非诺的添加可以以协同方式显著提高伊拉非诺的活性并达到高达60%的抑制(与此相比使用5μM伊拉非诺时为40%)。相反,CVC与苯扎贝特的组合揭示出低得多的EOB分值(图8A和8B),并且所有组合均未给出统计显著的结果。
总而言之,本申请人发现了ELA与CVC的组合的出人意料的抗纤维化活性。这些结果表明,式(I)的化合物与CVC的组合可以是协同的,并且能够在多种类型的疾病例如纤维化疾病中提供治疗益处。
实施例4:伊拉非诺与塞隆塞比(SEL)、GKT-831或GS-0976(GS)的组合:在小鼠纤维
化–NASH模型中的评估(8周)
在喂食增补有2%胆甾醇、30%乳脂饮食的缺乏胆碱、l-氨基酸限定饮食(CDAA)和饮用水中的高果糖玉米浆55(55%果糖/45%葡萄糖,终浓度为42g/L)(Mells等,J NutrBiochem 2015)(CDFF饮食)的小鼠中,评估了伊拉非诺与塞隆塞比、GKT-831或GS-0976的组合的预防效果。将5-6周龄雄性C57Bl/6J小鼠喂食对照(CSAA)饮食(n=4)、CDFF(n=12)或增补有单独的或组合的伊拉非诺(1或3mg/kg/天)、塞隆塞比(30mg/kg/天)、GKT-831(60mg/kg/天)或GS-0976(10mg/kg/天)的CDFF(每组n=8)共8周。
每周两次监测体重、食物和水摄入量。在治疗的最后一天,在6h禁食期后从眶后采血获得血浆样品并将小鼠处死。快速剖出肝脏用于生物化学和组织学研究。所有动物程序按照标准流程并根据实验室动物的适当护理和使用的标准推荐来进行。
组织学
组织包埋和制片
将肝薄片在4%福尔马林溶液中固定。然后,将肝块在PBS中清洗30分钟,并在乙醇溶液(70、80、95和100%乙醇的连续浴)中脱水。将所述肝块在三种不同的二甲苯(Sigma-Aldrich cat#534056)浴中温育,然后在两个液体石蜡浴中温育(59℃)。然后将肝块置于样品架中,轻柔地填充以完全覆盖所述组织。
将含有组织块的石蜡块从样品架取出并储存在室温。将肝块切成3μm薄片。
苏木精/曙红/番红染色
将肝切片脱石蜡化、重新水化并在Mayer’s苏木精(Microm,cat#F/C0303)中温育3分钟。然后,将所述肝切片在水中漂洗并在曙红Y0.5%乙醇(VWR,cat#1.02439.0500)和赤藓红0.5%溶液(VWR,cat#1.15936.0010)中温育1分钟,并在乙醇中漂洗。然后将切片在番红中温育2分钟,最后脱水并使用CV封片介质(Leica,cat#046430011)封片。
天狼猩红染色
将肝切片脱石蜡化、重新水化并在固绿FCF 0.1%(Sigma-Aldrich,cat#F7258)溶液中温育15分钟,然后在0.5%乙酸(Panreac,cat#131008.1611)浴中漂洗。然后,将所述肝切片在水中漂洗,并在0.1%天狼猩红(Direct Red 80,Fluka cat#43665)在饱和水性苦味酸(Sigma-Aldrich cat#P6744)中的溶液中温育30分钟。然后将切片脱水,并使用CV封片介质(Leica,cat#14046430011)封片。
组织学检查
对每个肝样本的来源不知情的技术员进行组织学检查。使用来自于3D Histech的Pannoramic 250扫描仪产生虚拟切片。对于每只动物,按照NASH临床研究网络(Kleiner2005,Brunt 1999)赋予概述了NASH的主要组织学病变的评分。简单来说,对脂肪变性,叶炎症和肝细胞鼓胀进行评分。为每个个体确立作为脂肪变性(0-3)、叶炎症(0-3)和鼓胀(0-2)损伤分级的未加权总和的NAFLD活动性评分(NAS评分)。
使用Quant Center软件(3D Histech,包括Pattern Quant和Histo Quant模块),对染色的胶原区域进行定量。简单来说,Pattern Quant被用于检测所述组织并测量它的表面。然后,将Histo Quant用于检测染色的胶原含量并在颜色阈值方法的基础上测量它的表面。然后将纤维化面积表示为每只动物的胶原表面占全部组织的百分率。
肝的生物化学分析
肝胶原含量的测量
肝胶原含量使用适合的QuickZyme试剂盒(总胶原测定法,cat#QZB-totcol2)来确定。所述测定法是基于羟脯氨酸的检测,这是一种主要存在于胶原三螺旋中的非蛋白质氨基酸。因此,组织水解物中的羟脯氨酸可用作组织中存在的胶原的量的直接度量(不区分前胶原、成熟胶原和胶原降解产物)。
在定量羟脯氨酸之前,需要将组织样品在6M HCl中在95℃下完全水解。所述测定法导致在570nm处具有最大吸收的发色体的产生。结果被表示为mg胶原/g肝脏。
肝甘油三酯含量的测量
将大约100mg冷冻的肝组织用组织匀浆器(24,Bertin Technologies,France)在含有15.4mM NaN3的150mM NaCl缓冲液中匀浆。用氯仿-甲醇(2:1,v/v)萃取匀浆液中的脂类级分,然后测量甘油三酯(Biolabo cat#80019)。
血浆前胶原III N-端前肽(PIIINP)测量
PIIINP的血浆浓度使用来自于Cloud-Clone Corp的ELISA测定法(cat#SEA573Mu),按照制造商的说明书来确定。将微孔板用特异性针对PIIINP的抗体预包被。将标准品或样品添加到具有特异性针对PIIINP的生物素偶联的抗体的适合的微孔板孔。接下来,向每个微孔板孔添加偶联到辣根过氧化物酶(HRP)的亲和素并温育。在添加TMB底物溶液后,只有那些含有PIIINP、生物素偶联的抗体和酶偶联的亲和素的孔表现出颜色变化。通过添加硫酸溶液终止所述酶-底物反应,并在450nm±10nm的波长处通过分光光度法测量颜色变化。然后通过将样品的OD与标准曲线进行比较来确定样品中PIIINP的浓度。结果以pg/mL为单位表述。
基质金属蛋白酶1(TIMP-1)的血浆组织抑制剂测量
血浆TIMP-1水平使用来自于R&D Systems(cat#MTM100)的定量夹心ELISA测定法,按照实验流程PRO_LIDO_000020来测量。简单来说,将特异性针对小鼠TIMP-1的单克隆抗体预包被在微孔板上。将标准品、对照和样品吸取到孔中,存在的任何小鼠TIMP-1被固定化的抗体结合。在洗掉任何未结合的物质后,向所述孔添加酶联接的特异性针对小鼠TIMP-1的多克隆抗体。在清洗以除去任何未结合的抗体-酶试剂后,向所述孔添加底物溶液。所述酶反应产生蓝色产物,其在添加终止溶液时变成黄色。测量到的颜色的强度与初始步骤中结合的小鼠TIMP-1的量成正比。然后从标准曲线推导出样品值。结果以pg/ml为单位表述。
肝基因表达分析
使用RNeasy小型试剂盒(Qiagen),遵照制造商的说明书从小鼠肝分离总RNA。使用M-MLV RT(莫洛尼鼠白血病病毒反转录酶)(Invitrogen cat#28025),在1x RT缓冲液(Invitrogen)、0.5mM DTT(Invitrogen)、0.18mM dNTP(Promega)、200ng pdN6(Amersham)和30U RNase抑制剂(Promega)中,将总RNA反转录成cDNA。
然后使用CFX96 TouchTM实时PCR检测系统(Biorad)进行定量PCR。简单来说,所述PCR反应以96孔板格式,在含有1μL反转录反应产物、0.5μL反向和正向引物(各10pmol)和12,5μl 2X iQ SYBR Green Supermix(BioRad)的25μl总体积中进行,使用了下述引物序列:
使用样品中作为参比看家基因的GAPDH基因的表达,将表达水平归一化。对于每种基因来说,通过选择最佳点(至少三个点)以便具有接近100%的PCR反应效率和接近1的相关系数,来绘制标准曲线。对于所述看家基因和靶基因两者来说,使用所述标准曲线方程确定表达水平(将每种靶基因的特定PCR效率考虑在内)。
结果和结论:
在最近的临床研究中,伊拉非诺、塞隆塞比、GKT-831和GS-0976已对NASH和纤维化终点显示出效果。我们想比较它们对相关NASH病理结果的作用并寻找所述组合的治疗益处。为了实现这个目的,通过用增补有胆甾醇和乳脂的缺少胆碱的L-氨基酸限定饮食和饮用水中的高果糖玉米浆(CDFF饮食)喂食C57Bl/6J小鼠,诱导了NASH。干预组中的动物在整个研究期间接受单独的伊拉非诺、塞隆塞比、GKT-831或GS-0976或它们与伊拉非诺的组合。NASH的发生通过组织学和生物化学测量以及参与NASH病理相关途径的基因的肝表达来评估。
喂食CDFF的小鼠发生NASH,并具有严重疾病的高度渗透。在所有动物中存在晚期脂肪变性和叶炎症,产生6或7的高NAS评分(图15-C)。与纤维化生成、组织重塑和炎症相关的基因的表达提高,并与以前在重症NASH患者中报道的基因特征相一致(图14-E-I)。
在这个模型中,伊拉非诺(3mg/kg/天)通过减少脂肪变性和肝叶炎症改善NASH组织学,导致NAFLD活动性评分的全面降低(未示出)。伊拉非诺也降低与炎症、组织重塑和纤维化生成相关的基因的表达(图14-E-I),引起通过组织学、肝胶原含量和血液中PIIINP和TIMP-1的释放所评估的肝纤维化的显著减少(图14-A-D)。
在这个模型中,单独的塞隆塞比(30mg/kg/天)改善肝纤维化,尽管程度比伊拉非诺低(图14)。伊拉非诺(3mg/kg/天)与塞隆塞比(30mg/kg/天)的组合对肝纤维化(通过组织学、肝胶原含量以及PIIINP和TIMP-1的释放来评估)并且对参与纤维化生成、组织重塑和炎症的基因的肝表达,产生协同的有益效果(图14)。
在这个模型中,单独的GKT-831(60mg/kg/天)对NASH和纤维化没有有益效果。然而,当与未达最适剂量的伊拉非诺(1mg/kg/天)组合时,它减少肝炎症浸润、NAFLD活动性评分和纤维化(图15)。
在这个模型中,使用GS-0976(30mg/kg/天)的治疗对肝脂肪和体重具有轻度有益效果(图16)。然而,与未达最适剂量的伊拉非诺(1mg/kg/天)的组合引起对全身脂肪燃烧的协同效果,导致20%的体重减轻和肝脂肪变性和甘油三酯含量的惊人减少(图16)。
总而言之,我们发现了伊拉非诺与MSDC-0602、PXS-4728、MT-3995(阿帕拉酮)、CF-102(纳莫德森)、维莫德吉、PBI-4050、吉卡宾、CP-640186、GS-0976、JKB-121(纳美芬)、VK-2809、MGL-3196、阿拉乔尔、恩利卡生、DUR-928(25-羟基胆甾醇-3-硫酸酯)、塞隆塞比、KD-025或GKT-831之间的协同效应。
参考文献
Brunt EM等,1999,Am J Gastroenterol;94(9):2467-74
Kleiner DE等,2005,Hepatology;41(6):1313-21
Claims (13)
1.一种组合产品,其包含:
(i)式(I)的化合物、其可药用盐或溶剂化物:
其中:
Y1表示卤素、Ra或Ga-Ra基团;
A表示CH=CH或CH2-CH2基团;
Y2表示Gb-Rb基团;
Ga和Gb相同或不同,表示氧原子或硫原子;
Ra表示氢原子、未取代的(C1-C6)烷基、被一个或多个卤素原子、(C1-C6)烷氧基或(C1-C6)烷硫基取代的(C6-C14)芳基或(C1-C6)烷基、(C3-C14)环烷基、(C3-C14)环烷硫基或杂环基;
Rb表示至少被–COORc基团取代的(C1-C6)烷基,其中Rc表示氢原子、或未取代的或被一个或多个卤素原子取代的(C1-C6)烷基、(C3-C14)环烷基或杂环基;并且
Y4和Y5相同或不同,表示未取代的或被一个或多个卤素原子取代的(C1-C6)烷基、(C3-C14)环烷基或杂环基;
和
(ii)抗NASH、抗纤维化或抗胆汁淤积药剂。
2.根据权利要求1所述的组合产品,其中组分(i)是伊拉非诺或其可药用盐。
3.根据权利要求1或2所述的组合产品,其中组分(ii)是ASK1抑制剂、双重NOX1和NOX4、VAP-1抑制剂、硬脂酰CoA去饱和酶-1抑制剂/脂肪酸胆汁酸缀合物、GPR84拮抗剂/FFAR1激动剂或免疫调节剂、mTOR调节剂或胰岛素增敏剂、THRβ激动剂、hedegehog信号传导途径抑制剂、腺苷A3受体激动剂、醛甾酮受体拮抗剂、TLR-4拮抗剂、半胱天冬酶抑制剂、ROCK2抑制剂或核受体配体。
4.根据权利要求1至3中任一项所述的组合产品,其中组分(ii)是塞隆塞比、GKT-831、PXS-4728A、阿拉乔尔、PBI-4050、MSDC-0602k、VK-2809、MGL-3196、维莫德吉、CF-102(纳莫德森)、MT-3995(阿帕拉酮)、JKB-121(纳美芬)、恩利卡生、KD-025和DUR-928,或其可药用盐。
5.根据权利要求1至4中任一项所述的组合产品,其中组分(ii)是GKT-831、阿拉乔尔、SHP-625、恩利卡生、沙罗格列扎、IMM-124-E、GS-9674、NGM-282、A-4250、GR-MD-02、GS-4997、F-351、索利霉素、瑞格列净、BTT-1023、IVA-337(兰尼兰诺)、JKB-121、KD-025、MSDC-0602、PBI-4050、PEG-FGF21、泰鲁司特、VK-2809、MGL-3196、GS-0976、颇得斯安、RG-125、伏昔巴特、吡格列酮、索马鲁肽、GSK2330672或MBX-8025。
6.根据权利要求1至5中任一项所述的组合产品,其中所述组合产品是包含组分(i)和(ii)和可药用载体的组合物。
7.根据权利要求1至6中任一项所述的组合产品,其中所述组合产品是包含组分(i)和(ii)的套装药剂盒,用于顺序、分开或同时使用。
8.根据权利要求1至7中任一项所述的组合产品,其中组分(i)和(ii)被配制在注射用悬液、凝胶、油、丸剂、片剂、栓剂、粉剂、胶囊、气溶胶、软膏、霜剂、贴片或用于延长和/或缓慢释放的盖伦形式中。
9.根据权利要求1至8中任一项所述的组合产品在制备药物中的用途。
10.根据权利要求1至8中任一项所述的组合产品在制备用于治疗炎性疾病、代谢疾病、纤维化疾病或胆汁淤积性疾病的药物中的用途。
11.根据权利要求10所述的用途,其中所述纤维化疾病选自:肝、肾、皮肤、表皮、内皮、肌肉、肌腱、软骨、心脏、胰腺、肺、子宫、神经系统、睾丸、阴茎、卵巢、肾上腺、动脉、静脉、结肠、肠(例如小肠)、胆道、软组织(例如纵隔膜或腹膜后腔)、骨髓、关节和胃的纤维化,特别是肝、消化道、肺、心脏、肾、肌肉、皮肤、软组织、骨髓、肠、眼和关节的纤维化。
12.根据权利要求10所述的用途,其中所述疾病选自:代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物引起的肝病、酒精引起的肝病、传染因子引起的肝病、炎性肝病、免疫系统功能障碍介导的肝病、血脂异常、心血管疾病、再狭窄、X综合征、代谢综合征、糖尿病、肥胖症、高血压、慢性胆管病变例如原发性硬化性胆管炎(PSC)、原发性胆汁性胆管炎(PBC)、胆道闭锁、3型进行性家族性肝内胆汁淤积症(PFIC3)、炎性肠病、克罗恩病、溃疡性结肠炎、瘢痕疙瘩、陈旧性心肌梗塞、硬皮病/系统性硬化症、炎性疾病、神经退行性疾病、癌症、肝癌、肝细胞癌、胃肠癌、胃癌、与神经纤维瘤病相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生性疾病、肥大细胞增多症、皮肤纤维肉瘤、包括乳腺、肺、甲状腺或结肠直肠癌在内的实体肿瘤、前列腺癌、任何起源的肝纤维化或硬化、代谢疾病引起的肝纤维化或硬化、NAFLD引起的纤维化或硬化、NASH引起的纤维化或硬化、酒精引起的肝纤维化或硬化、药物引起的肝纤维化或硬化、传染因子引起的肝纤维化或硬化、寄生虫感染引起的肝纤维化或硬化、细菌感染引起的肝纤维化或硬化、病毒感染引起的纤维化或硬化、HBV感染引起的肝纤维化或硬化、HCV感染引起的肝纤维化或硬化、HIV感染引起的肝纤维化或硬化、HCV和HIV双重感染引起的肝纤维化或硬化、放疗或化疗引起的纤维化或硬化、胆道纤维化、由任何慢性胆汁淤积性疾病造成的肝纤维化或硬化、任何病因的消化道纤维化、克罗恩病引起的纤维化、溃疡性结肠炎引起的纤维化、肠(例如小肠)纤维化、结肠纤维化、胃纤维化、皮肤纤维化、表皮纤维化、内皮纤维化、由硬皮病/系统性硬化症造成的皮肤纤维化、肺纤维化(lung fibrosis)、慢性炎性气道疾病例如COPD、哮喘、肺气肿、吸烟者的肺、肺结核继发的肺纤维化、肺纤维化(pulmonaryfibrosis)、特发性肺纤维化(IPF)、心脏纤维化、肾纤维化、肾原性系统性纤维化、肌肉纤维化、软组织(例如纵隔膜或腹膜后腔)纤维化、骨髓纤维化、关节纤维化(joint fibrosis)、肌腱纤维化、软骨纤维化、胰腺纤维化、子宫纤维化、神经系统纤维化、睾丸纤维化、卵巢纤维化、肾上腺纤维化、动脉纤维化、静脉纤维化、眼纤维化、心内膜心肌纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化(煤工尘肺的并发症)、增殖性纤维化、增生性纤维化、植入体周纤维化和石棉肺、关节纤维化(arthrofibrosis)、粘连性关节囊炎。
13.根据权利要求10所述的用途,其中所述疾病选自:代谢性肝病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、药物引起的肝病、酒精引起的肝病、传染因子引起的肝病、炎性肝病、免疫系统功能障碍介导的肝病、血脂异常、心血管疾病、再狭窄、X综合征、代谢综合征、糖尿病、肥胖症、高血压、慢性胆管病变例如原发性硬化性胆管炎(PSC)、原发性胆汁性胆管炎(PBC)、胆道闭锁、3型进行性家族性肝内胆汁淤积症(PFIC3)、炎性肠病、克罗恩病、溃疡性结肠炎、肝癌、肝细胞癌、胃肠癌、胃癌、结肠直肠癌、代谢疾病引起的肝纤维化或硬化、NAFLD引起的纤维化或硬化、NASH引起的纤维化或硬化、酒精引起的肝纤维化或硬化、药物引起的肝纤维化或硬化、传染因子引起的肝纤维化或硬化、寄生虫感染引起的肝纤维化或硬化、细菌感染引起的肝纤维化或硬化、病毒感染引起的纤维化或硬化、HBV感染引起的肝纤维化或硬化、HCV感染引起的肝纤维化或硬化、HIV感染引起的肝纤维化或硬化、HCV和HIV双重感染引起的肝纤维化或硬化、放疗或化疗引起的纤维化或硬化、胆道纤维化、由任何慢性胆汁淤积性疾病造成的肝纤维化或硬化、任何病因的消化道纤维化、克罗恩病引起的纤维化、溃疡性结肠炎引起的纤维化、肠(例如小肠)纤维化、结肠纤维化、胃纤维化、肺纤维化(lung fibrosis)、慢性炎性气道疾病例如COPD、哮喘、肺气肿、吸烟者的肺、肺结核继发的肺纤维化、肺纤维化(pulmonary fibrosis)、特发性肺纤维化(IPF)。
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PH12019502348A1 (en) | 2020-12-07 |
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IL269829A (en) | 2019-11-28 |
CN110536682B (zh) | 2023-01-06 |
WO2018193006A1 (en) | 2018-10-25 |
CA3058542A1 (en) | 2018-10-25 |
AU2018253885B2 (en) | 2024-04-11 |
KR20190136079A (ko) | 2019-12-09 |
MX2019012534A (es) | 2020-08-17 |
CA3057940A1 (en) | 2018-10-25 |
WO2018193007A1 (en) | 2018-10-25 |
EP3612176A1 (en) | 2020-02-26 |
IL269829B (en) | 2022-05-01 |
SG11201909168VA (en) | 2019-11-28 |
JP7266531B2 (ja) | 2023-04-28 |
BR112019021914A2 (pt) | 2020-05-26 |
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