CN111225666A - 用于治疗、预防或改善肝纤维化的γ-酮醛清除剂的组合物和使用方法 - Google Patents
用于治疗、预防或改善肝纤维化的γ-酮醛清除剂的组合物和使用方法 Download PDFInfo
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Abstract
描述了用于治疗、减弱、预防或改善个体的肝纤维化的方法和组合物。本发明的化合物是γ‑酮醛清除剂。
Description
本申请要求2017年9月5日提交的美国申请序列号62/554,294的优先权，其整体援引加入本文。
发明背景
1.领域
本发明涉及包含γ-酮醛清除化合物诸如2-羟基苄胺(2-HOBA)的组合物，以及给药γ-酮醛清除剂来治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展或改善肝纤维化的方法。
2.背景
肝纤维化是由肝炎症和/或慢性损伤引起的组织学变化。对肝的损伤导致肝星状细胞变得过于活跃并引发细胞外基质(ECM)合成增加。过量的胶原纤维沉积发生在肝细胞的细胞外空间，这导致肝细胞失去血液输注并变硬。纤维化是许多肝病的常见方面，并且定义为肝中瘢痕组织的形成。多种病因引起肝纤维化，包括但不限于肝炎、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、毒素、酒精性肝病(ALD)、遗传病症、胆汁淤积性病症和自身免疫性疾病。肝纤维化的指标包括纤维化组织的沉积和纤维发生级联的活化。纤维化可导致肝组织的永久性瘢痕化，这被称为肝硬化。
在NASH的情况下，有两个特点组织学特征：肝炎症和纤维化。尽管不存在FDA批准的NASH治疗剂，但已经研究了几种潜在的选择；其中最有前景的包括维生素E、噻唑烷二酮类和己酮可可碱。这些治疗剂中的每一种都显示了一些临界的临床效力，但是所有都受到它们潜在的副作用和/或毒性的限制，并且重要的是，这些治疗剂都没有改善纤维化，纤维化是NASH死亡率的最强指标。
γ-酮醛(γ-KA，也称为isolevuglandin或异酮醛(isoketal))是高反应性的脂质醛，其迅速与赖氨酸残基和磷脂酰乙醇胺反应形成加合物。在肝病的几种动物模型以及患有NASH的人中已经观察到γ-KA脂质和蛋白质加合物。来自患有NASH的人的初步数据也表明肝中升高的γ-KA-蛋白质加合物形成，并且γ-KA-蛋白质加合物类似地诱导肝损伤。γ-KA-蛋白质加合物与蛋白质功能的丧失、线粒体功能障碍、ER应激和促炎性细胞因子表达有关。
据发现，荞麦的主要物质2-羟基-苄胺(2-HOBA或水杨胺)是γ-KA的有效清除剂，清除γ-KA比γ-KA-蛋白质加合物的形成速率快980倍。研究表明2-HOBA比赖氨酸与γ-KA的反应性高980倍。重要的是，他们显示这种γ-KA清除剂不抑制环氧合酶。研究表明2-HOBA显著保护HepG2细胞免受H2O2诱导的细胞毒性。
最近发现γKA诱导人肝星状细胞(HSC)活化为促炎/促纤维化表型。占固有肝细胞的～10％的HSC在正常健康肝中是静止的。然而，响应肝损伤，HSC活化并转分化为增殖性、炎性肌成纤维细胞，其特征在于细胞外基质产生增强。因此，活化的HSC是公认的肝中主要的纤维化细胞，并且在慢性肝损伤状态中强烈提示肝纤维化的进展。氧化应激，特别是脂质氧化的产物，对HSC具有直接的促炎/促纤维化作用。Longato等人最近通过将原代人HSC暴露于合成的15-E2-isolevuglandin(15-E2-IsoLG)而将γKA鉴定为新的HSC活化剂。暴露于15-E2-IsoLG的非细胞毒性水平促进HSC活化，如上调的α-SMA表达、MAPK活化和增加的细胞因子产生所证实。
不受理论或机制的约束，本发明人已发现选择性清除剂γKA减弱、减少、治疗肝纤维化、减缓肝纤维化的进展和/或改善肝纤维化。此外，本发明的组合物不存在与现有的用于治疗肝病诸如NASH的治疗剂相关联的副作用或毒性。
例如，本发明的异酮醛清除剂是诸如水杨胺(SA)的化合物及其类似物。
本发明包括使用γ酮醛清除剂(包括2-HOBA)来清除有毒的氧化脂质(酮醛)，以治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展或改善肝纤维化。
发明概述
本发明的一个目的是提供用于治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展和/或改善肝纤维化的组合物。
本发明的另一个目的是提供治疗量或有效量的本发明化合物的制剂以治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展或改善肝纤维化的症状和/或减轻肝纤维化症状的严重性。
本发明的另一个目的包括提供新的营养疗法，其治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展或改善肝纤维化。该营养疗法可用于改善肝整体健康并支持健康的肝功能。
本发明的另一个目的包括提供2-HOBA(或者称为水杨胺)、SAM、2-羟基苄胺和戊基吡哆胺(PPM)的组合物和使用方法。
附图简述
图1a-1b是载玻片的图像，描绘了对照和2-HOBA处理的小鼠中纤维化的天狼猩红染色。
图2是描绘对照和2-HOBA处理的小鼠中的纤维化评分的图示。
图3描绘了通过qRT-PCR的基因表达谱。
发明详述
本文引用或提及的所有出版物通过援引加入以公开和描绘与引用的出版物有关的方法和/或材料。
本文所述的组合物用于治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展和/或改善肝纤维化。
治疗量或有效量是治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展或改善肝纤维化症状和/或减轻肝纤维化症状的严重性的本发明化合物的制剂。
本发明包括新的营养疗法，其治疗、预防、减弱、减少肝纤维化、减缓肝纤维化的进展或改善肝纤维化。该营养疗法可用于改善肝整体健康并支持健康的肝功能。
本发明包含使用一类双功能亲电试剂(BFE)“清除剂”分子来特异性防止肝中γKA-加合物形成的方法。包括吡哆胺及其水溶性衍生物2-HOBA(荞麦种子的天然产物)的一系列酚胺构成优选实施方案。特别地，2-HOBA比赖氨酸与IsoLG的反应快980倍，从而防止体外和体内的蛋白质和脂质加合。
本发明包括2-HOBA(或者称为水杨胺)、SAM、2-羟基苄胺和戊基吡哆胺(PPM)的组合物和使用方法。
本发明化合物的实例包括但不限于选自下式的化合物或其类似物及其药用盐：
其中：
R是N或C；
R2独立地为H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R2、R3和R4取代，并且可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R3是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R4是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R5是键、H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R4环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
及其立体异构体和类似物。
本发明的另一个实施方案包括下式的化合物，以及它们在用于治疗、预防或改善患有肝纤维化或有肝纤维化风险的个体的肝纤维化的方法中的用途：
其中：
R是N或C；
R2独立地为H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R2、R3和R4取代，并且可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R3是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R4是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R5是键、H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R4环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；及其立体异构体和类似物。
在某些实施方案中，化合物可以选自本文公开的化合物。在优选的实施方案中，化合物可以是水杨胺。
本发明的另一个实施方案是治疗、预防或改善患有肝纤维化或有肝纤维化风险的个体的肝纤维化，从而抑制或治疗肝纤维化的方法，所述方法包括向个体联合给药有效治疗哺乳动物功能障碍的剂量和量的至少一种化合物和治疗、预防或改善肝纤维化的具有已知副作用的药物的步骤，所述化合物具有由下式化合物代表的结构：
其中：
R是N或C；
R2独立地为H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R2、R3和R4取代，并且可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R3是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R4是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R5是键、H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R4环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；及其立体异构体和类似物。
可与本文公开的方法一起使用的化合物的实例包括但不限于选自下式的化合物：
其中：
R是N或C；
R2独立地为H、取代或未取代的烷基；
R3是H、卤素、烷氧基、羟基、硝基；
R4为H、取代或未取代的烷基、羧基；及其药学上可接受的盐。
在优选的实施方案中，化合物是水杨胺(2-羟基苄胺或2-HOBA)。
化合物可以选自：
或其药学上可接受的盐。
化合物也可以选自：
或其药学上可接受的盐。
化合物或类似物也可选自：
或其药学上可接受的盐。
化合物也可以选自：
或其药学上可接受的盐。
化合物也可选自
或其药学上可接受的盐。
本发明的化合物可以通过任何方法给药，并且这样的方法是本领域技术人员公知的，并且包括但不限于口服给药、透皮给药、吸入给药、鼻腔给药、局部给药、阴道内给药、眼部给药、耳内给药、脑内给药、直肠给药和肠胃外给药，包括如静脉内给药、动脉内给药、肌内给药和皮下给药的注射给药。化合物可以治疗性给药，以治疗存在的疾病或病状，或预防性地用于预防疾病或病状。
尽管包含组合物的任何合适的药物介质可以在本发明的上下文中使用，但优选地，组合物与合适的药物载体(如葡萄糖或蔗糖)组合。
计算给药组合物频率的方法是本领域公知的，并且可以在本发明的上下文中使用任何合适的给药频率(例如，每天一次6g剂量或每天两次3g剂量)，并且经任何合适的时间段(例如，单次剂量可以经5分钟的时间段或经1小时的时间段给药，或者多剂量可以经延长的时间段给药)。本发明的组合物可以经延长的时间段给药，如数周、数月或数年。组合物可以每天给药包含一个或多于一个剂量(单个供应物(serving))的单个供应物，以使每天的供应包含在一天或24小时中给药的组合物的总量。
任何本发明组合物的合适剂量均可以在本发明的上下文中使用。计算适当剂量的方法是本领域公知的。
“治疗”是指患者的医疗管理，其旨在治愈、改善、稳定或预防疾病、病理病状或病症。该术语包括积极治疗，即专门针对改善疾病、病理病状或病症的治疗，并且还包括病因治疗，即针对消除相关联的疾病、病理病状或病症的原因的治疗。此外，该术语包括姑息治疗，即旨在缓解症状而不是治愈疾病、病理病状或病症的治疗；预防性治疗，即旨在最小化或部分或完全抑制相关联的疾病、病理病状或病症发展的治疗；和支持性治疗，即用于补充另一种针对改善相关联的疾病、病理病状或病症的具体治疗方法的治疗。
“预防”或“防止”是指避免、拖延、停止或阻碍某些事情发生，包括通过预先的行为。治疗和预防有重叠。
“有效量”是指足以达到所期望的结果或对不期望的病状有作用的量。
“取代的”被认为包括有机化合物的所有容许的取代基。在广泛方面，容许的取代基包括有机化合物的非环状和环状的、支链和无支链的、碳环和杂环的以及芳族和非芳族的取代基。示例性的取代基包括例如下面所述的那些。对于适当的有机化合物，容许的取代基可以是一个或多个，并且可以相同或不同。出于本公开的目的，杂原子如氮可具有满足杂原子化合价的氢取代基和/或本文所述的有机化合物的任何容许的取代基。本公开不意在以任何方式受限于有机化合物的容许的取代基。此外，术语“取代”或“被……取代”包括隐含的条件，即这样的取代符合被取代原子和取代基的允许的化合价，并且该取代产生稳定的化合物，例如，不自发进行转化(诸如通过重排、环化、消除等)的化合物。
本文所用的“烷基”是1至24个碳原子的支链或非支链饱和烃基，诸如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、新戊基、己基、庚基、辛基、壬基、癸基、十二烷基、十四烷基、十六烷基、二十烷基、二十四烷基等。烷基可以是环状或非环状的。烷基可以是支链或非支链的。烷基也可以是取代或未取代的。例如，烷基可以被一个或多个基团取代，包括但不限于本文所述的任选取代的烷基、环烷基、烷氧基、氨基、醚、卤素、羟基、硝基、甲硅烷基、磺基-氧代或硫醇。“低级烷基”是含有1至6个(例如1至4个)碳原子的烷基。
“烷基”通常用于指未取代的烷基和取代的烷基；然而，本文还通过确定烷基上的具体取代基来具体提及取代的烷基。例如，术语“卤代烷基”具体是指被一个或多个卤素例如氟、氯、溴或碘取代的烷基。术语“烷氧基烷基”具体是指被一个或多个烷氧基取代的烷基，如下所述。术语“烷基氨基”具体指被一个或多个如下所述的氨基取代的烷基等。当在一种情况下使用“烷基”且在另一情况下使用特定术语诸如“烷基醇”时，并不意味着暗示术语“烷基”不会也指特定术语诸如“烷基醇”等。
该实践也用于本文所述的其他基团。也就是说，虽然术语诸如“环烷基”是指未取代的和取代的环烷基基团，但是取代的基团可以另外在本文中具体地确定；例如，特定的取代的环烷基可以指例如“烷基环烷基”。类似地，取代的烷氧基可以具体地指例如“卤代烷氧基”，特定的取代的烯基可以是例如“烯基醇”等。同样，使用上位术语诸如“环烷基”和下位术语诸如“烷基环烷基”的实践并不意味着暗示该上位术语不会也包括该下位术语。
本文所用的“环烷基”是由至少三个碳原子组成的非芳族碳基环。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基等。术语“杂环烷基”是如上定义的一类环烷基，并且包括在术语“环烷基”的含义内，其中环的至少一个碳原子被杂原子诸如但不限于氮、氧、硫或磷替代。环烷基和杂环烷基可以是取代的或未取代的。环烷基和杂环烷基可以被一个或多个基团取代，基团包括但不限于本文所述的任选取代的烷基、环烷基、烷氧基、氨基、醚、卤素、羟基、硝基、甲硅烷基、磺基-氧代或硫醇。
本文所用的“聚亚烷基”是具有两个或更多个彼此连接的CH2基团的基团。聚亚烷基可由式-(CH2)a-表示，其中“a”是2至500的整数。
本文所用的术语“烷氧基(alkoxy)”和“烷氧基(alkoxyl)”是指通过醚键键合的烷基或环烷基；即，“烷氧基”可以定义为-OA1，其中A1是如上定义的烷基或环烷基。“烷氧基”还包括如上描述的烷氧基的聚合物；即，烷氧基可以是聚醚，诸如-OA1-OA2或-OA1-(OA2)a-OA3，其中“a”是1至200的整数，并且A1、A2和A3是烷基和/或环烷基。
如本文所用的术语“胺”或“氨基”由式NA1A2A3表示，其中A1、A2和A3可以独立地是氢或如本文所述的任选取代的烷基、环烷基、烯基、环烯基、炔基、环炔基、芳基或杂芳基。
本文所用的术语“羟基”由式～OH表示。
本文所用的术语“硝基”由式～NO2表示。
试验例
实施例1
DIAMOND(非酒精性脂肪肝病的饮食诱导动物模型)是一种专有的等基因小鼠品系，其依次发展为由于高脂肪、高糖饮食的非酒精性脂肪肝病、非酒精性脂肪性肝炎、纤维化和肝细胞癌。DIAMOND小鼠的疾病进展与人类疾病进展独特地相似，包括组织病理学。
将12只8周龄雄性DIAMOND小鼠置于自由采食高脂肪饮食(Harlan-ENVIGOTD.88317)和含有葡萄糖(18.9％w/v)和果糖(23.1％w/v)的水中；在整个研究方案中，所有小鼠都保持这种饮食。在12周龄时，将小鼠分成两组：1)2-HOBA(n＝6)，以及2)载体对照(n＝6)。2-HOBA组中的动物在饮用水中接受2-HOBA(具有葡萄糖和果糖的1g/L水)。载体对照组接受不含2-HOBA的水(含葡萄糖和果糖)。每周测量体重和食物摄取。在～23周龄时，所有动物进行葡萄糖耐量试验(GTT)和MRI成像以评估肝脂肪。对于GTT，将动物禁食12小时，然后通过口服管饲法施用葡萄糖(在无菌水中2g/kg体重的100mg/mL葡萄糖)。在葡萄糖施用后0、15、30、45、60、90和120分钟时对血液取样，并计算曲线下面积。在24周龄时(2-HOBA或载体处理12周)处死动物。收集组织和血清用于分析。
肝切片用苏木精和伊红(用于评分脂肪变性、肝细胞气球样化和炎症)和天狼星红(用于评价纤维化)染色。使用以下标准1，以不知情的方式对脂肪变性、气球样化、炎症和坏死进行评分，脂肪变性(0-4)：0＝<5％；1＝5-25％；2＝25-50％；3＝50-75％；4＝75-100％。气球样化(0-3)：0＝不存在；1＝轻度(局灶性涉及少于3个肝细胞)；2＝中度(局灶性涉及超过三个肝细胞或多灶性)；3＝突出(多灶性，具有两个以上的三个或更多个肝细胞的病灶)。炎症(0-4)：0＝不存在；1＝最小(每20×场，0到1个病灶)；2＝轻度(两个病灶)；3＝中度(三个病灶)；4＝严重(四个或更多病灶)。测量葡萄糖、丙氨酸转氨酶和天冬氨酸转氨酶的血清水平。经由RT-qPCR评估以下基因的肝mRNA表达：Tnfa、Nlrp1a、Il1b、Il18、Timp1、Col1a1、ProCard、Nlrp3、Casp1、ProIl1b、Tgfb1、Bambi、Pdk4和Gapdh。双尾独立样品t检验用于比较2-HOBA和载体处理组之间的终点。显著性设定为α＝0.05。
图1a-b显示对照和2-HOBA处理的DIAMOND小鼠肝的天狼猩红染色。评分定义为0至4级。所有(4只中的4只)未处理小鼠的纤维化评分为1。2-HOBA处理的小鼠中的3只为0分，而其余2只为1分。
图2显示对照和2-HOBA处理的DIAMOND小鼠的纤维化评分。尽管肝脂肪变性和肝细胞气球样化程度相似，但与载体处理的DIAMOND小鼠相比，2-HOBA中纤维化的发生率显著更低(p＝0.03)。
图3显示通过qRT-PCR的基因表达谱，包括肝炎症和纤维化进展中关键基因的测量。金属蛋白酶组织抑制剂(TIMP)水平的升高抑制金属蛋白酶(MMP)，其使得细胞外基质蛋白诸如胶原在肝组织中积累。2-HOBA降低DIAMOND小鼠中肝Timp1 mRNA表达，解释了观察到的2-HOBA对纤维化进展的有益作用。此外，Col1a1 mRNA表达水平倾向于较低。该差异统计学上不显著(p＝0.08)。
观察到的2-HOBA对肝纤维化的有益作用是预料不到和令人惊讶的，因为许多NASH治疗剂未能改善纤维化严重性。肝纤维化严重性是唯一独立预测肝相关发病率和死亡率的NASH因子，因此能够预防或减弱纤维化进展的治疗剂可以显著改善NASH患者的结果。认为20HOBA治疗NASH的机制是通过减弱肝中的炎症变化。然而，纤维化是具有不同发病机制的第二阶段(secondary stage)发病机制。2-HOBA独立地减弱DIAMOND小鼠的肝纤维化而不改变炎症标记。因此，本文所述的结果是预料不到和令人惊讶的。
实施例2
γ-KA诱导肝星状细胞(HSC)的活化，HSC是肝纤维化的主要驱动因子。防止HSC活化为促炎/促纤维化表型可以抑制肝纤维化的进展。由于HSC向肌成纤维细胞样细胞的转化被认为是肝纤维化所必需的，使用结蛋白(HSC的标记)和α-平滑肌肌动蛋白(SMA)(活化HSC的标记)通过在固定的肝切片上的免疫组织化学来测量HSC活化。
实验设计：所有实验都在24小时血清饥饿的HSC上进行。为了防止γKA加合至培养基成分，在暴露的前15分钟在无氨基酸和脂质的Hank缓冲盐溶液中开始实验处理。以前已经确定这种暴露持续时间是人HSC良好耐受的。在暴露于0.5μM的15-E2-IsoLG之前，将人HSC与多剂量(1-500μM)的2-HOBA或载体预孵育。进行用2-HOBA和15-E2-levuglandin的时程实验以确定预处理和15-E2-IsoLG暴露的最佳持续时间。15-E2-IsoLG暴露后，收集培养基、洗涤细胞并刮取用于mRNA和蛋白质分析。制备单独的重复板用于ROS测量。
人HSC：人星状细胞得自ZenBio(Research Triangle Park,NC)并在HSC完全培养基(补充有20％胎牛血清、2mM谷氨酰胺、1X非必需氨基酸、1mM丙酮酸钠和1X抗生素-抗真菌剂的Iscove改良的DMEM)中培养。在第3到5代之间的细胞上进行全部实验。
15-E2-isolevuglandin：按照我们的顾问先前的描述来合成DMSO中合成的15-E2-IsoLG。
终点：RNA：使用RT2 ProfilerTM PCR阵列(Qiagen,Frederick,MD)和基于单基因探针的qRT-PCR基因表达测定，视情况而定，测量与纤维化活化、细胞因子产生和粘附分子相关的选定转录物的表达。蛋白质：免疫印迹分析用于测定关键细胞信号通路(ERK1/2、JNK、NFκB和p38 MAPK)的含量和活化状态。细胞因子：在用15-E2-IsoIG和2-HOBA孵育后收集的培养基中测定炎性细胞因子浓度。ROS/RNS：使用5-(和-6-)-羧基-2'-7'-二氯二氢荧光素二乙酸酯(羧基-H2)荧光探针(ThermoFisher Scientific)测量细胞内ROS/RNS形成。通过用Hoechst 33342对细胞核染色观察总细胞分布。通过荧光显微镜获得图像。
统计学：所有实验均一式三份进行。通过单向(剂量)或双向(剂量×时间)ANOVA(适合于设计)和Bonferroni多重比较试验对数据进行分析。
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Claims (8)
1.用于治疗、预防或改善患有肝纤维化或有肝纤维化风险的个体的肝纤维化，从而抑制或治疗所述肝纤维化的方法，所述方法包括向所述个体给药有效治疗哺乳动物功能障碍的剂量和量的至少一种化合物和治疗、预防或改善肝纤维化的具有已知副作用的药物的步骤，所述化合物具有由下式化合物代表的结构：
其中：
R是N或C；
R2独立地为H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R2、R3和R4取代，并且可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R3是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R4是H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R5环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；
R5是键、H、羟基、卤素、硝基、CF3、C1-6烷基、C1-6烷氧基、C3-10环烷基、含有C、O、S或N的C3-8元环，其任选地被一个或多个R4取代，R2和R3可以与一个或多个R2、R3或R4环化，以形成含有C、O、S或N的任选地被取代的C3-8元环；及其立体异构体和类似物。
2.权利要求1所述的方法，其中所述化合物选自下式：
其中：
R是N或C；
R2独立地为H、取代或未取代的烷基；
R3是H、卤素、烷氧基、羟基、硝基；
R4为H、取代或未取代的烷基、羧基；及其药学上可接受的盐。
3.权利要求1所述的方法，其中所述化合物是水杨胺(2-羟基苄胺或2-HOBA)。
4.权利要求1所述的方法，其中所述化合物选自下式：
或其药学上可接受的盐。
5.权利要求1所述的方法，其中所述化合物选自下式：
或其药学上可接受的盐。
6.权利要求1所述的方法，其中所述化合物选自下式：
或其药学上可接受的盐。
7.权利要求1所述的方法，其中所述化合物选自下式：
或其药学上可接受的盐。
8.权利要求1所述的方法，其中所述化合物选自下式：
或其药学上可接受的盐。
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| US201762554294P | 2017-09-05 | 2017-09-05 | |
| US62/554,294 | 2017-09-05 | ||
| PCT/US2018/049576 WO2019050967A1 (en) | 2017-09-05 | 2018-09-05 | COMPOSITIONS AND METHODS OF USING GAMMA-KETOALDEHYDE SENSORS TO TREAT, PREVENT, OR IMPROVE LIVER FIBROSIS |
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| JP (1) | JP7441170B2 (zh) |
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| CN110177771A (zh) * | 2016-09-06 | 2019-08-27 | 代谢科技有限公司 | 用于治疗、预防或改善非酒精性脂肪肝病(NAFLD)、NASH、ALD或肝相关病状的γ-酮醛清除剂的组合物和使用方法 |
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| CN103796648A (zh) * | 2011-07-12 | 2014-05-14 | 范德比尔特大学 | 用γ-醛酮清除剂治疗炎症和高血压的方法 |
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| IT1181871B (it) * | 1985-04-01 | 1987-09-30 | Consiglio Nazionale Ricerche | Inibitori selettivi delle benzilamminossidasi rispetto ad altre amminossidasi |
| WO2017033119A1 (en) * | 2015-08-25 | 2017-03-02 | Rao M Surya | Compositions and methods for the treatment of liver metabolic diseases |
| CA3035897A1 (en) | 2016-09-06 | 2018-03-15 | Metabolic Technologies, Inc. | Gamma-ketoaldehyde scavengers and compositions thereof for use in treatment of liver diseases |
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| CN103796648A (zh) * | 2011-07-12 | 2014-05-14 | 范德比尔特大学 | 用γ-醛酮清除剂治疗炎症和高血压的方法 |
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| L. LONGATO ET AL.: "Role of gamma-ketoaldehydes as novel mediators of experimental fibrogenesis and stellate cells activation", 《UNITED EUROPEAN GASTROENTEROLOGY JOURNAL》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110177771A (zh) * | 2016-09-06 | 2019-08-27 | 代谢科技有限公司 | 用于治疗、预防或改善非酒精性脂肪肝病(NAFLD)、NASH、ALD或肝相关病状的γ-酮醛清除剂的组合物和使用方法 |
| CN110177771B (zh) * | 2016-09-06 | 2022-12-13 | 代谢科技有限公司 | 用于治疗、预防或改善非酒精性脂肪肝病(NAFLD)、NASH、ALD或肝相关病状的γ-酮醛清除剂的组合物和使用方法 |
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| MX2020002441A (es) | 2020-09-03 |
| MX2022014099A (es) | 2022-12-08 |
| EP3678650A4 (en) | 2021-05-19 |
| US20190099387A1 (en) | 2019-04-04 |
| EP3678650A1 (en) | 2020-07-15 |
| CA3074736A1 (en) | 2019-03-14 |
| AU2018330416A1 (en) | 2020-04-02 |
| WO2019050967A1 (en) | 2019-03-14 |
| JP2020532591A (ja) | 2020-11-12 |
| BR112020004372A2 (pt) | 2020-09-08 |
| JP7441170B2 (ja) | 2024-02-29 |
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