CN111116684A - 一种具有甲状腺激素受体激动剂特性的肝靶向化合物及其药物组合物 - Google Patents
一种具有甲状腺激素受体激动剂特性的肝靶向化合物及其药物组合物 Download PDFInfo
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- CN111116684A CN111116684A CN201911407857.4A CN201911407857A CN111116684A CN 111116684 A CN111116684 A CN 111116684A CN 201911407857 A CN201911407857 A CN 201911407857A CN 111116684 A CN111116684 A CN 111116684A
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Abstract
Description
技术领域
本发明属于生物医药领域,具体涉及靶向药物领域,更具体地说,本发明涉及一种具有甲状腺激素受体激动剂特性的肝靶向化合物及其药物组合物。
背景技术
作为一种慢性肝病,非酒精性脂肪性肝病(NAFLD)的特征是肝细胞内脂质的过度积累,主要是甘油三酸酯(TGs)的过度积累。NAFLD的病变过程包括一系列肝脏的病理变化,从肝细胞内简单的甘油三酯积累(肝脂肪变性)到炎症性和肝细胞球囊性损伤,发展成非酒精性脂肪性肝炎(NASH),最终导致肝纤维化和肝硬化。脂肪变性向脂肪性肝炎转变的确切机制尚不清楚。有双打击的假说:第一次打击涉及肝细胞中TGs的积累,导致代谢功能障碍的恶性循环。一旦肝脂肪变性的存在被确定,进展为脂肪性肝炎涉及氧化应激起关键作用的第二次打击。目前NAFLD/NASH是一种在世界范围内越来越普遍的慢性肝病,并且趋于年轻化。公开资料显示,NAFLD全球发病率为15%~30%,其中10%~20%会发展成为NASH。据不完全统计,2016年中国约有2.4亿NAFLD人群,到2030年,预计NAFLD人群将增加到约3.1亿,其中患有肝硬化的患者将达到约230万。在美国,《自然》杂志2017年的一篇文章指出,NASH已经成为继慢性丙型肝炎之后肝移植的第二大原因,并预计在2020年实现超越,登顶美国肝移植的首要原因。之所以造成如此局面,主要原因在于,目前NASH尚无公认的药理学治疗方法及人们对这类疾病的不重视。目前,NASH已知的主要发病因素包括肥胖、2型糖尿病、高血脂及高血压等代谢综合征。全球范围内尚未出现针对该适应症的治疗药物获批上市。目前治疗干预的方法主要是基于生活方式的改变,包括饮食和运动,但效果并不明显。
甲状腺激素T4和T3具有多种作用,是调节糖、脂代谢和体重的有效物质。特别是,他们发挥了重要肝脂质稳态作用。他们发挥生理效应通过绑定到其特异的核受体,甲状腺激素受体TR-α和TR-β。通过与广泛分布在全身的特定激素受体TR-α和TR-β相互作用而产生影响。TR-β主要集中在肝脏表达,对脂质代谢有重要影响,包括降低低密度脂蛋白(LDL)胆固醇和甘油三脂,减少全身肥胖和体重(Pramfalk C等,Biochim Biophys Acta1812:929-937),并且可以通过提高肝脏的脂质代谢率来降低脂质含量。Perra A等的一项研究结果表明,T3可以抑制肝细胞脂肪变性,并修复已脂肪变性的肝细胞(Perra A等,FASEB J 22:2981-2989)。但是,过量的甲状腺激素容易引起副作用,副作用包括促甲状腺激素TSH、心脏以及骨骼和肌肉的不良反应(Braverman LE等,editors.Lippincott:TheThyroid 2000:515-517)及肝功能的损伤,从而导致ALT、AST及GGT等肝酶的升高。促甲状腺激素(TSH)是由腺垂体分泌的激素,腺垂体分泌促甲状腺激素,一方面受下丘脑分泌的促甲状腺激素释放激素(TRH)的促进性影响,另一方面又受到甲状腺激素反馈性的抑制性影响,二者互相拮抗,它们组成下丘脑-腺垂体-甲状腺轴。
促甲状腺激素TSH主要负责调节甲状腺细胞的增殖、甲状腺血液供应以及甲状腺激素的合成和分泌,在维持正常甲状腺功能中起最重要的调节作用。垂体本身的疾病可以直接影响到TSH的合成和释放。当甲状腺本身原因导致甲状腺激素合成和分泌异常时,也可影响到垂体TSH的分泌和血清TSH水平。同样,下丘脑疾病影响到TRH分泌时也会影响垂体的TSH的分泌和血清TSH水平。
促甲状腺激素TSH的主要作用就是控制甲状腺。它能促进甲状腺激素的合成,还能促进已生成的甲状腺激素释放入血。对甲状腺本身的生长和新陈代谢也起着重要作用,外源性的甲状腺激素进入体内,可使促甲状腺激素出现类似甲状腺激素反馈性的抑制性影响,从而影响促甲状腺激素的正常分泌,容易引发甲亢现象,出现心率加快或TSH降低的现象。临床中,一个药物如果使心率加快15%和使促甲状腺激素TSH降低30%,就说明了这个药物对心脏和甲状腺有副作用。有文献研究证明,T3引发心率加快15%的ED15以及抑制促甲状腺激素TSH 30%的ED30与降低高胆固醇TC的ED50的比值分别为1.5和0.4(GARY J等,Endocrinology 145(4):1656-1661),所以外源性甲状腺激素虽然显现出良好降脂和抑制肝细胞脂肪变性的效果,但其并不适合作为临床调节脂质代谢或NASH治疗的药物。由于甲状腺激素的这些不利影响,限制了其在脂质代谢及NASH治疗方面的进一步应用。如果能够消除或减少甲状腺激素对甲状腺轴及心脏和其他脏器的副作用,就可以获得能够预估的治疗效果。
甲状腺激素β受体激动剂,是一类基于甲状腺激素T3结构改造的新化合物或他们的前体化合物。甲状腺激素是通过与各种组织中的甲状腺激素受体TR-α和TR-β的结合,对机体的分化发育和代谢平衡进行调节。甲状腺激素β受体激动剂可以选择性作用于TR-β1的亚型TR-β1,对TR-β1的亲和力和选择性远大其对TR-α的作用。TR-β1存在于大多数组织中,尤其是肝脏,在心脏中分布较少,其介导了甲状腺素在肝脏和脂肪组织的作用。基于甲状腺激素T3结构改造的新化合物或他们的前体化合物保留了甲状腺激素上述作用,且呈现出较少的TR-α方面及对肝功能的副作用,目前是治疗非酒精性脂肪肝(NAFLD)新药的重要开发领域。
为了减少用于治疗NAFLD或NASH的药物的副作用,在生物医药领域迫切需要开发出一种新药,该新药既能够保持甲状腺素在肝内的脂质代谢作用,又不会到其他组织导致相应的副作用。
发明内容
本发明的一个目的是提供一种具有甲状腺激素受体激动剂特性的肝靶向化合物。
本发明的另一个目的是提供一种制备具有甲状腺激素受体激动剂特性的肝靶向化合物的方法。
本发明的又一个目的是提供一种具有甲状腺激素受体激动剂特性的肝靶向化合物的应用。
本发明的再一个目的是提供一种包含具有甲状腺激素受体激动剂特性的肝靶向化合物的药物组合物。
为了实现上述目的,本发明的一个方面提供了一种具有甲状腺激素受体激动剂特性的肝靶向化合物,其为式(1)所示的化合物:
其中,n为1-10的整数,优选为1-3的整数;X为羰基;Y为氨基或氧原子。
在本发明的一个实施方案中,式(1)所示的化合物优选为化合物GBL-0603:
外源性甲状腺激素进入体内,会进行全身分布,从而引发对甲状腺轴、心脏、肌肉、骨骼及肝功能的副作用。
N-乙酰半乳糖胺对肝脏中去唾液酸糖蛋白受体(ASGPR,一种肝细胞特异性表达的受体)具有高亲和力。可以使结构中含有半乳糖胺的化合物具有主动肝靶向性,可以使甲状腺激素β受体激动剂在其自身具有高的TR-β1的亲和力和选择性的基础上,还具有主动肝靶向,进一步减少其它组织的分布,减少其副作用。
本发明提供的具有甲状腺激素受体激动剂特性的肝靶向化合物中左侧末端含有三个半乳糖胺结构,右侧末端是一个T3类似结构,通过酯化或酰胺化连接,使整个化合物不仅具有肝靶向性和保持甲状腺激素β受体激动剂的作用,还最大限度地减少了副作用的发生。
本发明的另一个方面提供了一种制备具有甲状腺激素受体激动剂特性的肝靶向化合物的方法,该方法包括使化合物A和化合物B(作为中间体或起始物料)之间形成酯或酰胺的步骤:
其中,n为1-10的整数,优选为1-3的整数;X1为-COOH;Y1为氨基或羟基;X1和Y1也可以是其它使化合物A和化合物B之间形成酯或酰胺的基团。
本发明的又一方面提供了具有甲状腺激素受体激动剂特性的肝靶向化合物在制备用于治疗和/或预防由甲状腺激素调节引起疾病的药物中的应用,其中,所述疾病包括肥胖、高血脂症、高胆固醇血症、糖尿病、非酒精性脂肪性肝及其肝炎、酒精性脂肪肝及其肝炎、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌。
在本发明的优选实施方案中,所述疾病为非酒精性脂肪性肝及其肝炎。
本发明的再一方面提供了一种用于治疗和/或预防由甲状腺激素调节引起疾病的药物组合物,该药物组合物包含治疗有效量的上述具有甲状腺激素受体激动剂特性的肝靶向化合物以及任选的药学上可接受的辅料,其中,所述药学上可接受的辅料包括肠道吸收促进剂,其包括中链脂肪酸钠盐、胆酸盐、环糊精及其衍生物、阳离子型聚合物、阴离子型聚合物及巯基化聚合物。
在本发明的一个实施方案中,所述中链脂肪酸钠盐为癸酸钠,优选地,所述具有甲状腺激素受体激动剂特性的肝靶向化合物与癸酸钠的重量比例为1:0.2~1:0.75。
在本发明的优选实施方案中,所述药物组合物的剂型为注射剂,或者为速释或慢释放的口服制剂。
本发明提供的化合物或药物组合物可用于哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺或者胃肠道等的途径给药。最优选的给药途径为口服。最优选的日剂量为0.08-10mg/kg体重,一次性服用,或0.08-5mg/kg体重,分次服用。不管采用何种服用方法,个人的最佳剂量应依据具体的治疗方案而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
综上所述,本发明提供的具有甲状腺激素受体激动剂特性的肝靶向化合物的优点有二:1)利用N-乙酰半乳糖胺对肝脏细胞表面的去唾液酸糖蛋白受体高亲增强对肝脏的靶向性,减少其在其他组织中的分布;2)利用T3结构类似物具有对TR-β的高亲和力作用;进而降低不必要的副作用。二者组合成一个完整的化合物,使之能够特异性进入到肝脏细胞发挥甲状腺激素受体激动剂的作用,调节脂质代谢、逆转肝脂肪变和炎症,减缓肝纤维化。
与现有技术相比,本发明提供的具有甲状腺激素受体激动剂特性的肝靶向化合物的技术效果如下:
目前国内外临床还没有一种正式用于治疗NAFLD或NASH的药物,本发明提供的具有甲状腺激素受体激动剂特性的肝靶向化合物具有甲状腺激素β受体的特性,还具有主动肝靶向性,克服了外源性甲状腺激素及早期甲状腺激素β受体激动剂虽然对β1受体有高的选择性,但其还是存在对甲状腺轴、心脏、肌肉、骨骼和肝功能的副作用,是一种极具市场潜力的药物。本发明提供的化合物GBL-0603能够有效的降低db/db小鼠血清的胆固醇(CHO)、低密度脂蛋白(LDL)、甘油三酯(TG)(图3、8);同时,化合物GBL-0603能够降低db/db小鼠肝内的CHO和TG(图4、9);病理组织检测显示肝内的脂肪病变随着剂量的增加而得到改善(图5);无论对db/db和正常小鼠都没有显现出对心脏、骨密度、骨的矿物质含量的影响(图6、10、11、12);化合物GBL-0603能明显减少db/db小鼠肝脏的重量。另外,与本发明人早期发明的化合物Kylo-0101相比,新开发的化合物GBL-0603对肝脏功能的影响更为轻微(图15、16);在各个剂量下GBL-0603甲状腺素轴的各个指标没有明显变动(图17)。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚,本发明提供如下附图说明:
图1为化合物B高分辨率质谱图;
图2为化合物GBL-0603高分辨率质谱图;
图3为实施例2中,GBL-0603降低db/db肥胖模型小鼠血清中的CHO、TG和LDLC效果图;
图4为实施例2中,GBL-0603降低db/db肥胖模型小鼠肝脏组织细胞内的CHO和TG效果图;
图5为实施例2中,GBL-0603HE染色肝脏切片病理组织学改变示例图;
图6为实施例2中,GBL-0603对db/db肥胖模型小鼠心脏重量的影响图;
图7为实施例2中,GBL-0603对db/db肥胖模型小鼠肝脏重量的影响图;
图8为实施例3中,GBL-0603对db/db肥胖模型小鼠血清中的CHO、TG和LDLC影响图;
图9为实施例3中,GBL-0603对db/db肥胖模型小鼠肝脏中的CHO和TG影响图;
图10为实施例4中,GBL-0603对正常小鼠骨密度影响图;
图11为实施例4中,GBL-0603对正常小鼠骨矿物质含量影响图;
图12为实施例4中,GBL-0603对正常小鼠心脏重量影响图;
图13为实施例4中,GBL-0603对正常小鼠肝脏重量影响图;
图14为实施例4中,GBL-0603对正常小鼠体重影响图;
图15为实施例4中,GBL-0603对正常小鼠肝功能影响图;
图16为实施例4中,Kylo-0101对正常小鼠肝功能影响图;
图17为实施例4中,GBL-0603对正常小鼠血清中T3、fT3、T4、fT4、TSH的影响图。
具体实施方式
以下实施例说明了本发明公开的一些实施方案,但并不局限于这些。此外,在提供具体实施方案时,本发明人预期了那些具体实施方案的应用。例如具有具体同类或类似化学结构的化合物,用于不同的肝源性疾病的治疗。
说明:
DMF的中文名称为N,N-二甲基甲酰胺;
HOBt的中文名称为1-羟基苯并三唑;
DIPEA的中文名称为N,N-二异丙基乙胺;
Pd/C的中文名称为钯活性炭;
TBTU的中文名称为O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸;
DCM的中文名称为二氯甲烷;
NBS的中文名称为N-溴代丁二酰亚胺;
n-BuLi的中文名称为正丁基锂;
TIPSCl的中文名称为三异丙基氯硅烷;
THF的中文名称为四氢呋喃;
MTBE的中文名称为甲基叔丁基醚;
TBAF的中文名称为四丁基氟化铵。
本发明中所涉及两种物质的比,在没有特别注明的情况下均指体积比;
本发明中所涉及的含量,在没有特别注明的情况下均指体积百分浓度。
实施例1:化合物GBL-0603的制备
1、化合物A的合成
1.1化合物A-c1的合成
向反应瓶内依次加入DMF(8mL)、cbz-6-氨基己酸(24mg)、HOBt(21.6mg)、dlSANC-c12(84mg)和DIPEA(53.5mg),加料完毕,室温搅拌反应过夜,TLC检测,反应合格,停止反应,进行后处理,加水淬灭,静止分相,水相用DCM萃取三次,20mL/次,合并有机相,用饱和氯化钠水溶液洗涤、无水硫酸钠干燥、浓缩、过柱纯化,得到白色固体72.8mg。
1.2化合物A的合成
向反应瓶内依次加入化合物A-c1(72.8mg)、甲醇15mL、Pd/C(3.4mg),进行真空/氢气置换,置换完毕,通入H2,40℃搅拌反应1.0h,TLC分析,反应合格,停止反应,过滤,除掉Pd/C,滤液进行浓缩,得到47mg的白色固体。
2、化合物B的合成
2.1化合物B-c1的合成
称量2-异丙基苯酚(30.3mg),溶于乙腈中(10mL),加入NBS(34.2mg),于35℃反应6h。反应液浓缩,再溶于石油醚(50mL),过滤除去不溶物,滤液分别用水(40mL)和吡啶(40mL)洗涤,无水硫酸钠干燥,过滤,旋蒸,所得残留物(50.5mg)溶于乙腈中(40mL),加无水碳酸钾(32.0mg),溴化苄(37.1mg),40℃反应5h。冷却,过滤,过柱得化合物B-c1(63.1mg)。
2.2化合物B-c2的合成
称量化合物B-c1(63.1mg),溶于无水THF(10mL),冰浴冷却,滴加1.0mol/L n-BuLi的正己烷溶液(5.0mL),反应3h,滴加DMF(1.5mL),再反应3h。饱和氯化铵淬灭(5mL),乙酸乙酯萃取(10mL),吡啶(10mL)洗涤。有机相用无水硫酸钠干燥,过滤,过柱得化合物B-c2(33.4mg)。
2.3化合物B-c3的合成
称量4-溴-3,5-二甲基苯酚(30.8mg),溶于二氯甲烷(50mL),加咪唑(18mg)。冷却,滴加TIPSCl(25.5mg),反应5h。再加二氯甲烷(50mL)稀释反应液,有机相分别用水(50mL)和吡啶(50mL)洗涤,无水硫酸钠干燥,旋蒸,过柱纯化,得化合物B-c3(33.4mg)。
2.4化合物B-c4的合成
称量化合物B-c3(36.1mg),溶于THF(60mL),冰浴中冷却,滴加1.0mol/L n-BuLi的正己烷溶液(4mL),反应3h后滴加化合物B-c2(33.4mg)的THF溶液(5mL),再反应3h,饱和氯化铵(20mL)淬灭,乙酸乙酯(20mL)萃取,吡啶(30mL)洗涤有机相,无水硫酸钠干燥,过滤,过柱得化合物B-c4(54.3mg)。
2.5化合物B的合成
称量化合物B-c4(54.3mg),溶解于THF(50mL),滴加1mol/L TBAF溶液(3mL),TLC显示反应完成后加乙酸乙酯(50mL),水洗(20mL),吡啶(20mL),无水硫酸钠干燥,过滤,旋蒸,得白色固体(23.3mg),溶解于DMF(5mL),冷却,加入碳酸铯(40.4mg),再加溴乙酸苄酯(15.9mg)。40℃反应4h后反应液用MTBE稀释(10mL),过滤,加水(20mL),水相用MTBE萃取(20mL*2),吡啶(20mL)洗涤合并的有机相。无水硫酸钠干燥,过滤,旋蒸,过柱,将其溶于醋酸中(5mL),加催化剂10%Pd/C(0.2g),室温加氢反应过夜,过滤,旋蒸,过柱得淡黄色固体化合物B(15mg),化合物B的高分辨率质谱图如图1所示。
3、GBL-0603的合成
3.1GBL-0603-c1的合成
依次向反应瓶内加入DMF(3.0mL)、化合物B(15mg)、TBTU(8.47mg)和DIPEA(20.2mg),反应6h。然后迅速加入化合物A(47mg),室温搅拌2h。HPLC检测,反应合格,结束反应。
3.2GBL-0603的合成
GBL-0603-c1反应液经HPLC中控检测合格后,在冰浴条件下,用1.0mol/L的氨水溶液调反应液pH值为8-10。料液pH值合格后,撤掉冰浴,室温搅拌,反应半小时进行HPLC中控分析,反应合格,用冰醋酸调料液pH值为7.0,料液pH值合格后,进行浓缩,蒸除反应液中的DMF,浓缩残物用35%乙腈/水溶解,过滤、冻干,得到29.47mg冻干品,GBL-0603的高分辨率质谱图如图2所示。
实施例2:GBL-0603对db小鼠脂质代谢作用影响的剂效研究
实验动物与饲养:
选取30只雄性7周龄(BKS-db)遗传肥胖小鼠模型。实验前小鼠需先适应环境一周,选择健康小鼠作为受试动物。IVC笼具饲养,饲养密度为5只/笼,每周更换两次垫料。实验动物房要求:室温22~24℃,相对湿度40~70%,自动照明,12h明暗交替(08点00分开灯,20点00分关灯),实验动物房标准符合中华人民共和国国标GB14925-2010。
药物配制方法:
准确称取GBL-0603 210mg,溶解于35mL溶剂中,配制成6mg/mL母液,各个剂量组依次使用该母液分别稀释3倍、10倍、30倍、66.7倍后按相同的给药剂量进行给药。每三天配制一次GBL-0603母液。母液配制后于4℃保存备用。
分组和给药方案:
实验操作:
实验开始前,采血检测各组小鼠的总胆固醇(CHO),称量体重根据体重随机分组。给药期间每日称量小鼠体重。末次给药后禁食6h,安乐各组小鼠,心脏采血,分离血清,检测血清中甘油三酯(TG)、总胆固醇(CHO)、低密度脂蛋白(LDLC)、ALT和AST水平。采血后,称量肝脏重量,取各组小鼠肝脏中叶的一部分液氮速冻,-80℃保存备用。另外将小鼠肝脏中叶固定后石蜡包埋。取心脏并称取心脏重量。检测肝组织中CHO和TG的含量。进行肝组织病理学检测:将全部小鼠进行切片及HE染色,对照用药前后肝细胞脂肪变、炎症化和气球样化。
实施例3:添加促进剂癸酸钠的药效研究
动物饲养与实施例2同。分组和给药方案如下:
备注:药A处方中未添加癸酸钠、B和C处方中分别添加20%和75%主药重量的癸酸钠。
试验操作:
G2/G3/G4按照药物重量计算好溶剂体积,加入溶剂,反复涡旋,溶解完全后使用。配制完成后,一小时内完成给药。
实验开始前,称量体重根据体重随机分组。末次给药后禁食6h,安乐各组小鼠,心脏采血,分离血清,检测血清中甘油三酯(TG)、总胆固醇(CHO)、低密度脂蛋白(LDLC),并检测肝组织中CHO和TG的含量。
实施例4:GBL-0603和Kylo-0101对正常小鼠甲状腺和肝酶的影响研究
66只(雌雄各半)C57BL/6J鼠。分组和给药方案如下表:
试验操作:
实验开始前,称量体重根据体重随机分组。给药期间每周一次称量小鼠体重。末次给药后禁食6h,安乐各组小鼠,心脏采血,分离血清,检测血清中空白组和GBL-0603给药组的T3、fT3、T4、fT4、TSH的含量;骨密度、体重、肝脏和心脏重量;肝酶ALT、AST及GGT。检测空白组和Kylo-0101给药组的肝酶ALT、AST及GGT。
Claims (10)
4.权利要求1或2所述的具有甲状腺激素受体激动剂特性的肝靶向化合物在制备用于治疗和/或预防由甲状腺激素调节失调引起疾病或者代谢性疾病的药物中的应用。
5.根据权利要求4所述的应用,其中,所述疾病包括肥胖、高血脂症、高胆固醇血症、糖尿病、非酒精性脂肪性肝及其肝炎、酒精性脂肪肝及其肝炎、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌。
6.根据权利要求4或5所述的应用,其中,所述疾病为非酒精性脂肪性肝及其肝炎。
7.一种用于治疗和/或预防由甲状腺激素调节失调引起疾病的药物组合物,该药物组合物包含治疗有效量的权利要求1或2所述的具有甲状腺激素受体激动剂特性的肝靶向化合物以及任选的药学上可接受的辅料。
8.根据权利要求7所述的药物组合物,其中,所述药学上可接受的辅料包括肠道吸收促进剂,其包括中链脂肪酸钠盐、胆酸盐、环糊精及其衍生物、阳离子型聚合物、阴离子型聚合物及巯基化聚合物。
9.根据权利要求8所述的药物组合物,其中,所述中链脂肪酸钠盐为癸酸钠,优选地,所述具有甲状腺激素受体激动剂特性的肝靶向化合物与癸酸钠的重量比例为1:0.2~1:0.75。
10.根据权利要求7-9中任一项所述的药物组合物,其中,所述药物组合物的剂型为注射剂,或者为速释或慢释放的口服制剂。
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CN114470217A (zh) * | 2020-11-24 | 2022-05-13 | 深圳微芯生物科技股份有限公司 | 预防和治疗代谢异常或炎症引起的组织损伤的药物组合物 |
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