CN116139127A - 一种酰胺类化合物在制备预防或治疗代谢综合征药物中的用途 - Google Patents
一种酰胺类化合物在制备预防或治疗代谢综合征药物中的用途 Download PDFInfo
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Abstract
本发明涉及生物医疗领域,具体涉及一种新型酰胺类化合物的尾加压素受体激动剂在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病并发症药物中的应用。本发明的化合物可特异性激活尾加压素受体,具有显著促进肝细胞葡萄糖吸收,降低血糖,降低肝细胞甘油三酯含量及减少肝细胞脂肪堆积的作用。
Description
技术领域
本发明涉及生物医药领域,具体涉及一类新的具有尾加压素受体(urotensin-2receptor,UT)激动剂活性的化合物。及用于预防或治疗以尾加压素II或尾加压素样肽低表达或活性降低为特征的病理生理疾病的用途。尤其是在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用。
背景技术
尾加压素II(U-II)是首先从虾虎鱼(Gillichthys mirabilis)的神经分泌系统中分离出来的多肽类物质,而后在人类中也克隆出了该多肽。U-II是高活性的内源性尾加压素受体(UT受体)肽激动剂。UT受体是一种G蛋白偶联受体,可通过Gαq信号转导。U-II等肽类是具有环状结构,含长度为11-15个氨基酸的多肽。人U-II(hU-II)为11个氨基酸的多肽。UT受体,也称为GPR14,参与血管收缩的调节。在哺乳动物中,U-II前体(UTS2)和UT受体基因(UTS2R)的mRNA广泛表达于中枢神经系统和周围组织,包括脑、肾、肝、肺、胰腺、骨骼肌和其他组织以及血管和心脏细胞。与广泛分布的U-II和UT受体相一致,尾加压素能系统与许多病理状态有关,包括动脉粥样硬化、心力衰竭、高血压、肾病和糖尿病。
随着对UⅡ系统机制研究的深入,以其为靶点的药物研发也是研究的重点,并有药物进入临床实验。目前UTR的激动剂及拮抗剂均有发现,研究较多的为拮抗剂,根据其物质特征可以分为多肽类和非肽类。针对的治疗适应症包括心血管、糖尿病、肿瘤等多个方面。常见的UTR肽类拮抗剂有:urantide、UFP-803、BIM-23127等,其中urantide最为常用。Urantide最初以心血管类疾病为适应症进行开发,但由于药效不甚理想,未进入临床实验。目前有研究表明,urantide在改善糖尿病方面具有一定的作用。其可以逆转U-II引起的ROS生成,恢复骨骼肌中胰岛素引起的葡萄糖转运体4(glucose transporter 4,GLUT4)向细胞膜的转运,促进骨骼肌的葡萄糖吸收,也可以降低UⅡ引起的炎症反应,改善IR的状态。常见的UTR非肽类拮抗剂有:GSK-1562590、AC-7954、GSK-1440115、palosuran等。其中palosuran是研究最为深入和广泛的UTR抑制剂,其在2003年以糖尿病肾病为适应症进入临床试验,但最终由于药效学不理想在2007年终止于Ⅱ期临床试验。有文献报道,palosuran可以改善糖尿病病人的肾病、心血管类疾病、肺损伤等。另有研究表明,U-II与胰岛素分泌减少、胰岛素信号通路损伤有关,但palosuran并未表现出逆转这一现象的作用,具体机制和原因还需要进一步探究。总体来说,以UTR为靶点的药物研究目前大多处于停滞状态,大多为疗效不明显的原因。我们研究发现,U-II本身可改善糖脂代谢,从另一方面解释了其拮抗剂的效果不良的原因,也说明尾加压素受体激动剂在对脂肪调节和糖耐量调节方面发挥重要作用。拓宽抗肥胖和2型糖尿病的选择领域因此开发新型具有尾加压素受体激动作用的药物至关重要。
代谢综合征是一组复杂的代谢紊乱症候群,是多种代谢成分异常聚集的病理状态,是导致糖尿病心脑血管疾病的危险因素。其具有以下特点:①多种代谢紊乱集于一身,包括肥胖、高血糖、高血压、血脂异常,这些代谢紊乱是心、脑血管病变以及糖尿病的病理基础;②有共同的病理基础,目前多认为它们的共同原因就是肥胖尤其是中心性肥胖所造成的胰岛素抵抗和高胰岛素血症;③可造成多种疾病累加,如高血压、冠心病、脑卒中、甚至某些癌症等。
肥胖是由体内过剩的能量在脂肪组织中过度堆积所引发的慢性代谢性疾病,是影响心脑血管疾病、糖尿病和肿瘤等的重大风险因素。限制能量摄入如节食、服用减肥药;或增加能量消耗如锻炼等策略因依从性差或药物副作用令肥胖症患者体重反弹,从而对减肥望而却步。因此,如何预防和治疗肥胖这一全球性健康问题,寻找安全有效的治疗方法成为国内外医学、营养学家致力研究的热点问题。
2型糖尿病是全球性流行的代谢性疾病,是心血管疾病的首要危险因素。在全球范围内,大约有3亿糖尿病患者,患者人数居高不下且仍不断上升,近年表现更甚。尤其在我国,随着我国人民生活水平的提高,饮食结构、生活习惯、环境条件等发生了巨大变化,与遗传、营养、代谢及环境等因素密切相关的糖代谢紊乱疾病的患病率急剧增加,且发展趋势尚未得到有效控制。由代谢性疾病引起的心脏、肾脏、脑和眼血管、神经等并发症不仅严重影响患者的生活质量,同时带来沉重的家庭和社会医疗负担。因此,2型糖尿病防治是我国目前面临的重大科学问题,探索防治糖代谢性疾病的有效措施,具有重要的科学价值和意义。
目前在临床上,治疗肥胖的药物主要包括食欲抑制剂:中枢抑制食欲药物,调节食欲的胃肠激素。作用于外周脂肪合成与分解的:作用在胃肠道减少脂肪吸收(脂肪酶抑制剂和钠-葡萄糖共转运体2抑制剂)。作用在脂肪组织减少脂肪合成、促进释放分解。2型糖尿病治疗的药物主要包括:胰岛素及其类似物、磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮衍生物、促胰岛素分泌剂、中成药等。目前仍没有可减少代谢综合征和并发症的减肥产品。
本发明所述的(1-苯基-N-[2-(2-噻吩基)乙基]环戊烷羧酰胺(化合物28565)),分子式为C18H21NOS,分子量为299.43,气压760托时的预测沸点为508.7℃。目前尚无关于化合物28565药理活性的研究。
本发明所述的化合物28565,是经过实验研究获得的新的发现。新的发明内容主要涉及制备药物和药物组合。为临床提供预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。尤其是在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用。目前有关化合物28565在尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。尤其是在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用方面直接或间接的治疗作用尚没有报道。
发明内容
本发明要解决的技术问题是,提供一种新的具有尾加压素受体激动剂活性的化合物在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用。
为解决本发明的技术问题,本发明提供如下技术方案:
(1)本发明提供了如式(I)所示的化合物(即化合物28565)在制备具有尾加压素受体激动剂活性的药物中的应用。
(2)本发明提供了如式(I)所示的化合物在预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的应用。
(3)本发明提供了如式(I)所示的化合物在制备治疗和/或预防代谢综合征药物中的应用。其中,所述的代谢综合征包括肥胖、糖尿病、糖尿病并发症、脂肪肝、血脂异常、高血压。所述的代谢综合征包括各种原因导致的人体的蛋白质、脂肪、碳水化合物发生代谢紊乱的病理状态。
所述的糖尿病包括1型及2型糖尿病;所述的肥胖包括先天性、后天性、药物性原因导致的肥胖;所述的糖尿病并发症是指糖尿病大、小血管病变;所述的脂肪肝包括各种原因导致的肝脂肪变性;所述的血脂异常包括高甘油三酯、低高密度脂蛋白血症、高胆固醇血症;所述的高血压包括收缩压和或舒张压升高,可伴或不伴有心、脑、肾器官的功能或器质性损害。
进一步的,所述的糖尿病并发症包括糖尿病肾病、糖尿病末梢循环功能障碍、糖尿病外周神经病变、糖尿病眼病、糖尿病肌病、糖尿病合并高脂血症。
(4)本发明提供了一种药物组合物在在制备具有尾加压素受体激动剂活性的药物中的应用,在制备预防或治疗以尾加压素II或尾加压素样肽低表达或活性降低为特征的病理生理或心理疾病药物中的应用,制备治疗和/或预防代谢综合征药物中的应用,其特征在于,所述的药物组合物含有有效剂量的如式(I)所示的化合物及药用赋形剂;所述的药物组合物包括控制释放、持续释放制剂及微粒体给药系统的形式。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95%(重量)。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重,优选为0.1-100mg/kg体重,更优选为1-60mg/kg体重,最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
有益技术效果
1.本发明化合物(I)可调节尾加压素受体活性。关于本发明化合物对尾加压素受体活性调节的用途是首次公开。
2.本发明化合物(I)可预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。关于本化合物对该用途方面的报道为首次公开。
3.本发明化合物(I)可制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的用途。关于本化合物在该方面的用途为首次公开,拓宽相关疾病的选择药物。
4.目前在国际上,关于尾加压素激动作用公开了在心血管调节方面的专利(美国专利,专利号4533654,专利日期1985年8月6日)。我们前期的研究首次报道尾加压素激动在改善代谢综合征、肥胖和2型糖尿病的作用(一种多肽在制备预防或治疗代谢综合征药物中的用途。申请号CN110038114A)。关于化合物28565对尾加压素系统方面的影响国际及国内未见相关论文及专利发表。
5.本发明的化合物(I)通过新型靶点,用于预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的用途。作为药物进行开发,具有明显的优益。
附图说明
图1.化合物28565与尾加压素受体蛋白模型的对接结果。
图2.化合物28565的ADMET预测结果。
图3.化合物28565可剂量依赖性激活尾加压素受体,其半数有效浓度为4.48*10- 8M。
图4.化合物28565对尾加压素受体的激活具有特异性,不激活其他GPCR受体。
图5.化合物28565对HepG2肝细胞葡萄糖吸收的影响。
图6.化合物28565对HepG2肝细胞的乳酸释放的影响。
图7.化合物28565对HepG2肝细胞活力的影响。
图8.化合物28565可改善油酸诱导的HepG2非酒精性脂肪肝细胞模型的脂质堆积。
图9.化合物28565可降低油酸诱导的HepG2非酒精性脂肪肝细胞内甘油三酯的合成。
具体实施方式
下面结合本发明进一步说明化合物(I)在调节尾加压素受体活性,预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的用途。
下述实施例更详细地举例说明本发明,并不是对本发明的任何限制。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
实施例1.化合物28565的溶解及使用
化合物28565,购自安捷凯生物医药公司(中国,武汉),货号:ajcz0113-300mg,采用化学合成法获得,LCMS纯度>97%。将化合物粉末溶解于DMSO中,配置成10mM的溶液,分装后,贮存于-80℃备用。使用时用生理盐水稀释至相应的浓度。
实施例2.化合物28565与尾加压素受体蛋白模型的对接
实验方法:在Discovery Studio中导入尾加压素受体蛋白结构的pdb文件和化合物28565的sdf文件,采用Discovery Studio中CDOCKER柔性对接方法进行蛋白-配体对接。首先,点击“Prepare Ligands”和“Prepare Protein”对化合物和蛋白进行处理,定义蛋白为受体分子,并预测受体结构的活性位点;运用“Receptor-Ligand Interactions”中的CDOCKER模块进行蛋白与化合物28565对接的操作,并设定相应参数。待程序运行结束后输出对接结果,对对接结果进行分析。
实验结果:分子对接是一种研究分子间(如配体和受体)相互作用,并预测其结合模式和亲合力的理论模拟方法,一般认为配体与受体结合的构象稳定时能量越低,发生的作用可能性越大。化合物28565与受体蛋白的结合能为-11.7203kcal/mol,提示化合物28565与受体的结合活性较高。化合物28565与受体生成的配体-蛋白相互作用二维平面图见图1,化合物28565分别与氨基酸残基Arg161和Lys163形成氢键作用,与氨基酸残基Leu370和Ala84形成疏水结合Pi-Alkyl作用,增加了分子与蛋白的作用。结果见图1。
实施例3.化合物28565的成药性评价
实验方法:用Discovery Studio软件中的ADMET模块,将化合物28565的sdf文件导入DS软件中,在“Small Molecules”模块中选定“Calculate Molecular Properties”点击ADMET descriptors进行参数设置,点击运行,对化合物的吸收、分布、代谢、排泄和毒性进行预测,获得化合物28565的被动肠内吸收性、25℃的水溶性、血脑屏障穿透性、人细胞色素CYP4502D6酶结合、肝毒性、血浆蛋白结合等方面的数据。
实验结果:ADMET预测结果见图2。化合物28565相对应的水溶性值logSW为-4.58,提示化合物28565具有良好的水溶性。化合物28565的CYP450 2D6酶的抑制数为0.21,小于界值0.5,故无抑制作用。化合物28565的肝毒性测定值为0.57,可能具有较弱的肝毒性。化合物28565与血浆蛋白结合值为3.84,未与血浆蛋白结合,为游离型,具有药物活性。化合物28565的血脑屏障通过率为0.55,具备良好的血脑屏障穿透性。结果见表1和图2。
表1化合物28565的ADMET预测结果
实施例4.化合物28565对尾加压素受体的激活作用
实验方法:HTLA细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到80%时,以1:3的比例传代培养。当细胞融合度达到70%时,弃去原培养基,换用8ml DMEM继续培养4h。4h后,从培养基中吸出4ml DMEM并补加4ml含10%胎牛血清的DMEM培养基。以每皿DMEM:UTR:PEI=800μl:10μg:40μl的比例配制转染液,转染试剂用量按照质粒浓度不同需要进行调整。将转染液混合均匀,静置15-20min后滴入细胞。细胞转染24h后,弃去原培养基,4mL生理盐水清洗两次,加入1mL胰蛋白酶后置于37℃培养箱中消化1-2分钟,将细胞转入离心管中,800r离心3分钟,弃去上清,加入10%胎牛血清的DMEM培养基,反复吹打细胞至细胞混匀,以1.5*105/孔接种至96孔板中,于37℃、5%CO2培养箱中培养24h。细胞种板24h后,将化合物28565储备液用生理盐水进行梯度稀释,使其终浓度分别为10-10M、10-9M、10-8M、10-7M、10-6M、10-5M,加入不同浓度的化合物28565 10μl/孔。细胞给药24h后,弃去培养液上清,加入Bright-Glo试剂50μl/孔,使用M5酶标仪检测化学发光强度。
实验结果:HTLA细胞给予不同浓度的化合物28565刺激后,在10-10M-10-5M范围内,化合物28565的激动作用呈现良好的浓度依赖关系,即随化合物28565的浓度升高,激动作用越强,经计算得化合物28565的半数有效浓度为4.48*10-8M。结果见表2和图3。
表2化合物28565对尾加压素受体的激活作用
实施例5.化合物28565对其他GPCR受体的激活作用
实验方法:HTLA细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到80%时,以1:3的比例传代培养。当细胞融合度达到70%时,弃去原培养基,换用8ml DMEM继续培养4h。4h后,从培养基中吸出4ml DMEM并补加4ml含10%胎牛血清的DMEM培养基。分别转染GPCR质粒FFA1,FFA2,FFA3,以每皿DMEM:M质粒:PEI=800μl:10μg:40μl的比例配制转染液,转染试剂用量按照质粒浓度不同需要进行调整。将转染液混合均匀,静置15-20min后滴入细胞。余下操作同实施例4。
实验结果:HTLA细胞给予不同浓度的化合物28565刺激后,只有转染UTS2R质粒的HTLA细胞的激活作用呈现出浓度依赖关系,而转染FFA1,FFA2,FFA3质粒的HTLA细胞则无明显的激活作用。这提示我们,化合物28565对尾加压素受体的激活具有特异性,而不激活其他GPCR受体。结果见表3和图4。
表3化合物28565对尾加压素受体的特异性激活作用
实施例6.化合物28565对HepG2肝细胞葡萄糖吸收的影响
实验方法:HepG2肝细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到90%时,用胰蛋白酶消化,以1:3的比例传代培养。取对数生长期的细胞以100μl/孔(1*105个/ml)接种于96孔板中培养24h,24h后,弃去原培养基,加入含10%胎牛血清的无酚红的1640培养基100μl/孔。同时将化合物28565储备液用生理盐水进行梯度稀释,使终浓度分别为10-9M、10-8M、10-7M、10-6M、10-5M,加入不同浓度的化合物28565 10μl/孔。继续培养48h后,每孔吸出10μl培养基上清加到新的96孔中,另加10μl标准对照品和10μl纯水;加入葡萄糖测试工作液R1 100μl/孔,混匀后置于37℃保温4min,于340nm处读取吸光度值;再加入葡萄糖测试工作液R2 25μl/孔,混匀后置于37℃保温5分钟min,于340nm处读取吸光度值。
实验结果:化合物28565作用48小时后,与对照组相比,在10-9M-10-5M范围内,对肝细胞HepG2葡萄糖吸收有明显促进作用,其中以10-6M和10-5M时的作用最为显著。结果见表4和图5。
表4化合物28565对HepG2肝细胞葡萄糖吸收的影响
实施例7.化合物28565对HepG2肝细胞乳糖释放的影响
实验方法:细胞培养,种板,给药的操作见实施例6。乳酸含量检测方法如下:细胞培养48h后,每孔吸出10μl培养基上清,稀释10倍后,取20μl加到新的96孔中,另加20μl标准对照品和20μl纯水;加入酶工作液50μl/孔,显色液10μl/孔,混匀后置于37℃气浴中准确反应10min;再加入终止液100μl/孔,充分混匀后于530nm处读取吸光度值。
实验结果:化合物28565作用48h后,与对照组相比,在10-9M-10-5M范围内HepG2肝细胞的乳酸含量显著性降低。结果见表5和图6。
表5化合物28565对HepG2肝细胞乳糖释放的影响
实施例8.化合物28565对HepG2肝细胞活力的影响
实验方法:细胞培养,种板,给药的操作见实施例6。细胞活力检测方法如下:细胞培养48h后,弃去原培养基,在96孔板中加入CCK8稀释液100μl/孔,并置于37℃培养箱中孵育约30min,于450nm处读取吸光度值。
实验结果:化合物28565作用48小时后,与对照组相比,在10-8M-10-5M范围内均可显著性降低HepG2肝细胞活力。结果见表6和图7。
表6化合物28565对HepG2肝细胞活力的影响
实施例9.化合物28565对油酸诱导的HepG2非酒精性脂肪肝细胞模型的脂质堆积的影响
实验方法:HepG2肝细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到90%时,用胰蛋白酶消化,以1:3的比例传代培养。取对数生长期的细胞以100μl/孔(6*104个/ml)接种于96孔板中培养24h,24h后,弃去原培养基,正常组加入含10%灭活胎牛血清的4.5g/L DMEM高糖培养液100μl/孔,模型组加入含0.25mM油酸的含10%灭活胎牛血清的4.5g/L DMEM高糖培养液100μl/孔,给药组加入含0.25mM油酸的含10%灭活胎牛血清的4.5g/L DMEM高糖培养液90μl/孔,同时将化合物28565储备液用生理盐水进行稀释,加入10μM化合物28565 10μl/孔。化合物28565与油酸共孵育24h后,弃去培养液,PBS洗1-2次,用4%多聚甲醛固定20-30min,油红O工作液室温染色1h,PBS洗3-5次后于显微镜下观察并拍照。
实验结果:经油酸诱导的HepG2肝细胞存在脂质堆积,化合物28565干预24h后,与模型组相比,HepG2肝细胞内红色脂滴显著性减少,提示化合物28565具有改善肝HepG2肝细胞脂质堆积的作用。结果见表6和图7。
表7化合物28565对油酸诱导的HepG2非酒精性脂肪肝细胞模型的脂质堆积的影响
实施例10.化合物28565对油酸诱导的HepG2非酒精性脂肪肝细胞内甘油三酯合成的影响
实验方法:HepG2肝细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到90%时,用胰蛋白酶消化,以1:3的比例传代培养。取对数生长期的细胞以2ml/孔(30*104个/ml)接种于6孔板中培养24h,24h后,弃去原培养基,正常组加入含10%灭活胎牛血清的4.5g/L DMEM高糖培养液2ml/孔,模型组加入含0.25mM油酸的含10%灭活胎牛血清的4.5g/L DMEM高糖培养液1.8ml/孔,给药组加入含0.25mM油酸的含10%灭活胎牛血清的4.5g/L DMEM高糖培养液1.8ml/孔,同时将化合物28565储备液用生理盐水进行稀释,加入10μM化合物28565 200μl/孔。化合物28565与油酸共孵育24h后,弃去上清,每孔加入100μl裂解液,收集细胞混匀后室温静置10min;取适量上清转移至1.5ml EP管中,70℃加热10min后,室温2000rpm离心5min;取上清样品10μl加190μl工作液,于550nm处检测吸光度值。
实验结果:经油酸诱导的HepG2肝细胞甘油三酯含量明显增多,化合物28565干预24h后,与模型组相比,HepG2肝细胞内甘油三酯含量显著性降低,提示化合物28565可减少肝细胞中甘油三酯的合成。结果见表7和图8。
表8化合物28565对油酸诱导的HepG2非酒精性脂肪肝细胞内甘油三酯合成的影响
Claims (9)
4.根据权利要求3的应用,其特征在于,所述的代谢综合征包括肥胖、糖尿病、糖尿病并发症、脂肪肝、血脂异常、高血压。
5.根据权利要求3的应用,其特征在于,所述的代谢综合征包括各种原因导致的人体的蛋白质、脂肪、碳水化合物发生代谢紊乱的病理状态。
6.根据权利要求4的应用,其特征在于,所述的糖尿病包括1型及2型糖尿病;所述的肥胖包括先天性、后天性、药物性原因导致的肥胖;所述的糖尿病并发症是指糖尿病大、小血管病变;所述的脂肪肝包括各种原因导致的肝脂肪变性;所述的血脂异常包括高甘油三酯、低高密度脂蛋白血症、高胆固醇血症;所述的高血压包括收缩压和或舒张压升高,可伴或不伴有心、脑、肾器官的功能或器质性损害。
7.根据权利要求4的应用,其特征在于,所述的糖尿病并发症包括糖尿病肾病、糖尿病末梢循环功能障碍、糖尿病外周神经病变、糖尿病眼病、糖尿病肌病、糖尿病合并高脂血症。
9.根据权利要求8的应用,其特征在于,所述的药物组合物包括控制释放、持续释放制剂及微粒体给药系统的形式。
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