CN113876769A - 一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用 - Google Patents
一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用 Download PDFInfo
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- CN113876769A CN113876769A CN202111168661.1A CN202111168661A CN113876769A CN 113876769 A CN113876769 A CN 113876769A CN 202111168661 A CN202111168661 A CN 202111168661A CN 113876769 A CN113876769 A CN 113876769A
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明公开了一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,提供的化合物J‑1063和J‑1048对小鼠肝纤维化指标的影响,通过腹腔注射TAA后,与正常组相比模型组肝纤维化指标水平增加,表明肝脏发生病变,化合物J‑1063和J‑1048的高、低剂量和阳性对照组明显降低肝纤维化指标水平,表明治疗效果显著。本发明采用上述一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,解决了现有技术中抗肝纤维化药物毒性大、选择性低、易产生耐药性的问题。
Description
技术领域
本发明涉及一类具有转化生长因子β1受体激酶(ALK5)抑制活性的衍生物用途技术领域,尤其是涉及一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用。
背景技术
肝纤维化(hepatic fibrosis)是由致病因素引起的病理生理过程。肝纤维化发生在任何肝损伤的修复和愈合过程中。肝纤维化是慢性肝炎的结果,最终导致肝硬化甚至肝癌(Y Yong,T Bai,YL Yao,et al.Upregulation of SIRT1-AMPK by thymoquinone inhepatic stellate cells ameliorates liver injury,Toxicol.Lett.2016,262,80-91.)。慢性乙型肝炎是高发的常见病,据统计目前全球肝炎病毒(Heptatitis B Virus,HBV)携带者有3.25亿人,我国现有约1.2亿乙型肝炎感染者。据统计,全世界每年有140万慢性肝病患者肝纤维化和肝硬化导致死亡,而我国又是肝病高发国家。因此,积极防治肝纤维化、肝硬化的发生和发展显得尤为重要和紧迫。
近年的研究表明,急、慢性肝损伤都会导致肝纤维化,肝纤维化进一步发展会导致肝硬化、肝功能衰竭及门脉高压或肝癌,最终导致死亡。目前只有肝移植来延续肝癌晚期患者的生命(W Chen,R Zheng,PD Baade,et al.Cancer statistics in China,CA Cancer JClin.2016,66,115-132.)。但是由于捐献器官的数目有限,只有很少一部分人适用。
近几十年来,抗肝纤维化药物研究取得了一定的进展,目前临床上多用中药或中成药进行抗肝纤维化的治疗,这些药物存在毒性大、选择性低、易产生耐药性的缺点。
转化生长因子β(TGF-β)在组织纤维化中起重要作用,如细胞外基质(Extracellular matrix,ECM)合成、活性氧(Reactive oxygen species,ROS)生成、肌成纤维细胞激活等。胶原蛋白(Collagen)和α-平滑肌肌动蛋白(α-SMA)的分泌是判断纤维化程度的主要标志,它们会通过纤维化细胞因子和其细胞内信号通路,调节TGF-β诱导的Smad激活和ROS信号。
TGF-β1是促进肝纤维化最有效的细胞因子,通过促进ECM的产生及沉积,而引起肝纤维化,其中TGF-β1/Smad信号传导通路调节ECM的基因表达是促进ECM生成的重要途径。
TGF-β的信号的传导需要通过两种类型的单跨膜丝氨酸(serine)/苏氨酸(threonine)受体激酶,这两种受体激酶分别为type I受体和type II受体(简称,TβR-I和TβR-II)。当TGF-β与受体结合时,TβR-I(ALK5)受体得以活化,活化的ALK5受体催化一类重要的信号分子Smad2和Smad3蛋白磷酸化,从而与受体分离,接着与共同调节剂Smad4接合成异聚物。这种Smad复合物转移到细胞核内,结合转录因子,调节ECM的基因转录因子的表达,促进ECM的过量生成及沉积,导致肝纤维化的发生。TGF-β信号的过表达导致多种人类疾病的发生,如血液系统恶性肿瘤、乳腺癌和纤维化等。由此可见,抑制ALK5与底物Smad2和Smad3的结合或抑制ALK5对Smad2和Smad3的磷酸化作用,进而阻断TGF-β的信号向细胞核的传导是非常有效的方法。
由于肝纤维化的主要特征是I型胶原蛋白为主的ECM成分过度沉积,故抑制I型胶原蛋白表达是目前抗纤维化治疗的重要策略之一。因此,开发强效地抑制ALK5激酶和胶原沉积的药物,必将在临床上有着良好的应用前景。
发明内容
本发明的目的是提供一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,解决了现有技术中抗肝纤维化药物毒性大、选择性低、易产生耐药性的问题。
为实现上述目的,本发明提供了一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,所述含吡啶结构的吡唑类衍生物的结构式如下:
其中:R1为4-(噻吩并[3,2-c]吡啶-2-基)或4-(苯并[c][1,2,5]噻二唑-5-基),R2为H或F,X为O或S。
优选的,含吡啶结构的吡唑类衍生物应用在制备抗肝纤维化药物中,在体外的激酶实验中通过抑制ALK5激酶阻断TGF-β信号通路。
优选的,含吡啶结构的吡唑类衍生物应用在制备抗肝纤维化药物中,在体内的动物实验中通过抑制细胞外基质沉积的表达显示明显的抗肝纤维化活性。
优选的,含吡啶结构的吡唑类衍生物为2-(4-(苯并[c][1,2,5]噻二唑-5-基)-3-(6-甲基吡啶-2-基)-1H-吡唑-1-基)-N-(3-氟苯基)乙基硫代酰胺(II,J-1048)或2-(3-(6-甲基吡啶-2-基)-4-(噻吩并[3,2-c]吡啶-2-基)-1H-吡唑-1-基)-N-苯基酰胺(III,J-1063),其中II,J-1048和III,J-1063的结构式如下:
优选的,2-(4-(苯并[c][1,2,5]噻二唑-5-基)-3-(6-甲基吡啶-2-基)-1H-吡唑-1-基)-N-(3-氟苯基)乙基硫代酰胺或2-(3-(6-甲基吡啶-2-基)-4-(噻吩并[3,2-c]吡啶-2-基)-1H-吡唑-1-基)-N-苯基酰胺应用在制备抗肝纤维化药物中,用于在体外抑制ALK5激酶的活性,结果显示,合成的两个化合物的抑制活性远高于阳性对照化合物LY-2157299(II期临床)。
因此,本发明采用上述一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,含吡啶结构的吡唑类衍生物不但可以制剂ALK5激酶,而且还可以调控α-SMA和CollagenⅠ的表达,同时,明显抑制纤维化程度和炎症细胞募集浸润。
下面通过附图和实施例,对本发明的技术方案做进一步的详细描述。
附图说明
图1为式II化合物(J-1063)的体内实验过程,其中D=Day,W=Week,TAA=Thioacetamide;
图2为式II化合物(J-1063)的体内实验体重变化;
图3为化合物J-1063对小鼠肝脏重量的影响;
图4为化合物J-1063对TAA模型小鼠血清中ALT和AST含量的影响;
图5为化合物J-1063对TAA模型小鼠肝脏组织的HE、Sirius Red及Masson染色分析;
图6为化合物J-1063对TAA模型小鼠肝脏组织的TUNEL法分析、TGF-β表达及肝纤维化标志水平;
图7为化合物J-1048对小鼠肝脏重量的影响;
图8为化合物J-1048对TAA模型小鼠血清中ALT和AST含量的影响;
图9为化合物J-1048对TAA模型小鼠肝脏组织的HE、Sirius Red及Masson染色分析;
图10为化合物J-1063对TAA模型小鼠肝脏组织的TUNEL法分析、TGF-β表达及肝纤维化标志指标水平。
具体实施方式
本发明提供了抗肝纤维化方面两种化合物的动物实验结果。以下实例中式II和III化合物由延边大学药学院药物合成实验室发表的论文中的方法制备得到(Eur.J.Med.Chem.2019,180,15-27)。
本发明提供的用于肝纤维化的药物,其化学名分别为:2-(3-(6-甲基吡啶-2-基)-4-(噻吩并[3,2-c]吡啶-2-基)-1H-吡唑-1-基)-N-苯基酰胺(II,J-1063)和2-(4-(苯并[c][1,2,5]噻二唑-5-基)-3-(6-甲基吡啶-2-基)-1H-吡唑-1-基)-N-(3-氟苯基)乙基硫代酰胺(III,J-1048),分子结构式为:
本发明提供了化合物J-1063和J-1048对硫代乙酰胺(Thioacetamide,TAA)模型小鼠血清中谷丙氨酸酶(ALT)和谷草转氨酶(AST)含量的影响。实验结果表明,腹腔注射TAA后,模型组与正常组相比ALT和AST水平显著升高,表明TAA可诱导小鼠肝脏损伤。化合物J-1063和J-1048的高、低剂量组血清中ALT和AST水平较模型组显著降低,并且它们显示与更高剂量的阳性对照组LY-2157299类似的水平(见图3、图4、图7、图8)。
本发明提供了化合物J-1063和J-1048对小鼠肝脏重量的影响。实验结果表明,通过腹腔注射TAA后,与正常组相比模型组肝重增加,表明肝脏发生病变。化合物J-1063和J-1048的高、低剂量和阳性对照组明显降低肝脏重量,表明治疗效果显著(见图3、图4、图7、图8)。
本发明提供了化合物J-1063和J-1048对TAA模型小鼠肝脏组织病理学变化。正常肝脏表面光滑呈鲜红色并伴有光泽。当给予TAA刺激后,小鼠肝脏成纤维化,肝脏表面失去光泽,并伴有颗粒感。当给予化合物J-1063或J-1048高、低剂量后,肝脏表面恢复红色光泽,颗粒感减少。
化合物J-1063对TAA模型小鼠肝脏组织病理学变化实验。
HE染色分析:目的是检测小鼠肝脏切片的组织病理学损伤程度。正常组肝小叶排列规则,肝脏细胞核呈圆形。而模型组肝小叶结构紊乱、纤维间隔增多并伴有大量炎性细胞浸润到汇管区。与模型组相比,通过J-1063低、高剂量和阳性对照(LY-2157299)治疗后,炎症细胞浸润明显减少,肝细胞排列趋于整齐,纤维间隔变窄,见图5的HE一行。
Sirius Red染色分析:目的是为了评估胶原沉积程度与分布情况。实验结果表明与正常组相比,模型组肝脏胶原分布明显,门静脉区发生纤维化,形成芒状纤维。不同剂量的J-1063减少了胶原沉积,且呈现剂量依赖性,见图5的Sirius red一行。
Masson染色分析:与正常组相比,模型组阳性区域明显增加,在门脉区可见有大量的胶原纤维沉积,形成纤维间隔,而J-1063高、低和阳性对照组明显改善了由TAA引起的胶原沉积,见图5的Masson一行。
TUNEL法分析:采用TUNEL法检测J-1063对肝细胞凋亡及黄褐色染色的影响。TAA暴露后,TAA组小鼠肝脏组织中多见凋亡细胞,而正常组小鼠肝组织中未见明显凋亡细胞。J-1063高、低和阳性组显著地降低了凋亡肝细胞的数量,见图6的TUNEL一行。
TGF-β表达:与正常组相比模型组中TGF-β阳性表达增高,出现大量棕褐色斑点。通过J-1063高、低和阳性对照治疗后棕褐色斑点减少,阳性表达降低,见图6的TGF-β一行。
肝纤维化指标水平:在正常组少见阳性表达,模型组在中央静脉周围及肝窦周围观察细胞呈棕黄色或棕褐色,表明存在增殖的肌成纤维细胞,肝纤维化的形成。与模型组相比,J-1063高、低或阳性对照组处理后明显改善α-SMA和Collagen I的阳性表达。J-1063高剂量组α-SMA和Collagen I表达平衡,与正常组相似,见图6的α-SMA和Collagen I两行。
J-1048对TAA模型小鼠肝脏组织病理学变化
HE染色分析:目的是检测小鼠肝脏切片的组织病理学损伤程度。正常组肝小叶排列规则,肝脏细胞核呈圆形。而模型组肝小叶结构紊乱、纤维间隔增多并伴有大量炎性细胞浸润到汇管区。与模型组相比,通过J-1048低、高剂量和阳性对照(LY-2157299)治疗后,炎症细胞浸润明显减少,肝细胞排列趋于整齐,纤维间隔变窄,见图9的H&E一行。
Masson染色分析:与正常组相比,模型组阳性区域明显增加,在门脉区可见有大量的胶原纤维沉积,形成纤维间隔。而J-1048高、低和阳性对照组明显改善了由TAA引起的胶原沉积,见图9的Masson一行。
Sirius Red染色分析:评估胶原沉积程度与分布情况。实验结果表明与正常组相比,模型组肝脏胶原分布明显,门静脉区发生纤维化,芒状纤维。不同剂量的J-1048减少胶原沉积,且呈现剂量依赖性,见图9的Sirius Red一行。
肝纤维化指标水平:α-SMA和CollagenⅠ在正常组少见阳性表达,模型组在中央静脉周围及肝窦周围观察细胞呈棕黄色或棕褐色,表明存在增殖的肌成纤维细胞,肝纤维化的形成。与模型组相比,J-1048高、低或阳性对照组处理后明显改善α-SMA和CollagenⅠ的阳性表达。J-1048高剂量组α-SMA和CollagenⅠ表达回落,与正常组相似,见图10的α-SMA和CollagenⅠ两行。
F4/80染色分析:一般认为F4/80是成熟巨噬细胞的特异性标志物。与正常组相比,TAA刺激下的F4/80阳性表达增加,表明巨噬细胞浸润;而与模型组相比,J-1048高、低和阳性对照组的阳性表达减少,炎性细胞浸润得到改善,见图10的F4/80一行。
过氧化物酶(MPO)染色分析:MPO为中性粒细胞活化标志物,其表达增高表明中性粒细胞浸润到病灶部位。与正常组相比TAA暴露下的MPO阳性表达增加,与模型组相比J-1048高、低和LY-2157299组的阳性表达减少,见图10的MPO一行。
实施例1
含吡啶结构的吡唑类衍生物的ALK5激酶抑制活性研究
ALK5激酶磷酸化抑制活性测定方法:ALK5蛋白来源于Sf9昆虫细胞中表达的人类重组GST-融合蛋白。激酶分析使用微孔容积为50μL的珀金埃尔默的96孔板。将依次加入20μL实验缓冲液(标准缓冲液),5μL ATP溶液(在H2O中),5μL测试化合物(溶解于10%DMSO中),20μL酶/底物来配制反应混合物。已配制的反应混合物在30℃孵育60min后,放置于50μL2%(V/V)H3PO4溶液中,除去测定缓冲液,用200μL 0.9%(W/V)氯化钠溶液洗涤2次。采用微平板闪烁计数器建立了Pi的掺入。激酶活性分析利用Beckman Coulter/SAGIANTM Core系统来检测。测定结果见表1。
表1式I化合物ALK5激酶抑制活性
式I化合物ALK5激酶半数抑制活性(IC50)测定结果如表1所示,合成的两个目标化合物的抑制活性远高于阳性对照化合物LY-2157299。
实施例2
式II化合物J-1063的体内实验:
体内实验中,选用8周龄C57BL/6J雄性小鼠,平均体重为20±1g,随机分成6组,每组6只,即正常组、硫代乙酰胺(Thioacetamide,TAA)模型组、J-1063低剂量组(TAA+J-1063-6.25mg/kg)、J-1063高剂量组(TAA+J-1063-12.5mg/kg)、阳性对照组(TAA+LY-2157299-50mg/kg)和单独给药组(J-1063-25mg/kg)。模型组、给药组通过TAA建立小鼠纤维化模型。第一周每周3次腹腔注射TAA-100mg/kg,后五周每周3次注射TAA-200mg/kg。再造模的第4周通过灌胃给予小鼠药物(J-1063或LY-2157299)连续两周,每天一次。42天后,处死小鼠,留取小鼠血清、肝脏组织(见图1和图2)。
实施例3
式III化合物J-1048的体内实验:
体内实验中,选用8-12周龄C57BL/6J雄性小鼠,平均体重为20±2g,随机分成6组,每组6只,即正常组、硫代乙酰胺(Thioacetamide,TAA)模型组、J-1048低剂量组(TAA+J-1048-12.5mg/kg)、J-1048高剂量组(TAA+J-1048-25mg/kg)、阳性对照组(TAA+LY-2157299-50mg/kg)和单独给药组(J-1048-25mg/kg)。模型组、给药组通过TAA建立小鼠纤维化模型。第一周周间3次腹腔注射TAA-100mg/kg,后五周每周3次注射TAA-200mg/kg。再造模的第4周通过灌胃给予小鼠药物(J-1048或LY-2157299)连续两周,每天一次。42天后,处死小鼠,留取小鼠血清、肝脏组织。
实施例4
生化指标分析:
小鼠末次给药四小时后进行麻醉眼球取血,室温放置30min后置于离心机中,4℃,3000rpm离心30min分离得血清,使用长春汇力生物有限公司ALT、AST试剂盒测定,操作方法依照说明书进行。
实施例5
HE染色:
苏木精-伊红染色法,简称HE染色法,是石蜡切片最常用的染色方法之一。苏木精染液为碱性,主要使细胞核的内的染色质与胞质内的核酸呈蓝紫色;伊红为酸性染料,主要使细胞质和细胞外基质的成分染成红色。在染色之前需对石蜡切片进行脱蜡,然后进行苏木素染色,待切片均匀染上色之后用PBS溶液进行返蓝,直至肝脏切片呈现蓝色,用自来水冲洗1min后进行伊红染色,将切片浸入尹红染料中2-3min后用自来水冲洗掉多余的伊红染料。染色结束后要对切片进行脱水,梯度浓度酒精由低至高浓度酒精依次脱水即可,脱水结束后将切片放入二甲苯中10min进行透明,最后用中性树胶进行封片。
实施例6
Masson三色染色:
Masson三色染色是胶原纤维染色的经典方法。肝脏切片常规脱蜡至水后进行染色,首先用Masson复合染色液染色5min,然后蒸馏水冲掉染液;滴加磷钼酸染液染色5min后甩干染色液,直接滴加苯胺蓝染色液染色5min。染色结束后进行脱水透明处理,最后用中性树胶进行封固。
实施例7
天狼星红染色(Sirius red):
将切片放置于80℃烤箱烘烤30min,室温冷却15min。切片浸入二甲苯处理3次,每次15min。切片依次浸入100%、95%、90%、85%乙醇各自5min;自来水小水流冲洗5min。配置1%天狼猩红使用液(0.1g天狼猩红+10mL苦味酸),染色1h后,双蒸水洗5min。切片依次浸入95%、100%乙醇各自2min。切片浸入二甲苯处理3次,每次2min。滴加适量中性树胶与组织,避免气泡盖上盖玻片,晾干,放置在倒置显微镜观察。
实施例8
免疫组化实验:
石蜡切片60℃烘片后,常规脱蜡至水。由于切片所用到的肝脏在福尔马林溶液中浸泡过,可能会生成醛键及羧甲基等物质,导致抗原决定簇的关闭。因此,需对切片进行抗原修复。本实验中采用的是微波炉加热抗原修复法,使用到的抗原修复液为枸橼酸钠缓冲液。抗原修复结束后每张切片滴加一滴过氧化氢溶液消除内源性过氧化氢酶。封闭非特异性抗原采用的是山羊血清,室温孵育30分钟。封闭结束后,分别在切片上加入一抗,二抗,然后用DAB进行染色。为了更明显的观察染色部位,一般用苏木素对切片进行复染。复染结束后,进行返蓝,最后依次脱水透明并封片。
因此,本发明采用上述一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,解决了现有技术中抗肝纤维化药物毒性大、选择性低、易产生耐药性的问题。
最后应说明的是:以上实施例仅用以说明本发明的技术方案而非对其进行限制,尽管参照较佳实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对本发明的技术方案进行修改或者等同替换,而这些修改或者等同替换亦不能使修改后的技术方案脱离本发明技术方案的精神和范围。
Claims (5)
2.根据权利要求1所述的一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,其特征在于:含吡啶结构的吡唑类衍生物应用在制备抗肝纤维化药物中,在体外的激酶实验中通过抑制ALK5激酶阻断TGF-β信号通路。
3.根据权利要求1所述的一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,其特征在于:含吡啶结构的吡唑类衍生物应用在制备抗肝纤维化药物中,在体内的动物实验中通过抑制细胞外基质沉积的表达显示明显的抗肝纤维化活性。
5.根据权利要求4所述的一种含吡啶结构的吡唑类衍生物在制备抗肝纤维化药物中的应用,其特征在于:2-(4-(苯并[c][1,2,5]噻二唑-5-基)-3-(6-甲基吡啶-2-基)-1H-吡唑-1-基)-N-(3-氟苯基)乙基硫代酰胺或2-(3-(6-甲基吡啶-2-基)-4-(噻吩并[3,2-c]吡啶-2-基)-1H-吡唑-1-基)-N-苯基酰胺应用在制备抗肝纤维化药物中,用于在体外抑制ALK5激酶的活性。
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CN109674791A (zh) * | 2019-02-12 | 2019-04-26 | 兰州大学 | 噻唑并吡喃酮类似物在制备抗肝纤维化或抗急性肝损伤药物中的应用 |
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CN109415346A (zh) * | 2016-06-30 | 2019-03-01 | 韩美药品株式会社 | 作为alk5抑制剂的新型吡唑衍生物及其用途 |
CN109674791A (zh) * | 2019-02-12 | 2019-04-26 | 兰州大学 | 噻唑并吡喃酮类似物在制备抗肝纤维化或抗急性肝损伤药物中的应用 |
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WEN-JING ZHU等: "Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl-pyridin-2-yl)pyrazole and 3(5)-(6-methylpyridin-2-yl)-4-(thieno-[3,2,-c]pyridin-2-yl)pyrazole derivatives", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 180, pages 15 - 27 * |
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