CN114099497A - 4-肉桂基-3-羟基吡咯酮类化合物在制备糖尿病治疗药物中的应用 - Google Patents
4-肉桂基-3-羟基吡咯酮类化合物在制备糖尿病治疗药物中的应用 Download PDFInfo
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Abstract
本发明属于糖尿病治疗药物技术领域,具体涉及4‑肉桂基‑3‑羟基吡咯酮类化合物在制备治疗和/或预防糖尿病药物中的应用。所述化合物如式(1)所示,R1选自氢、卤素、C1‑8烷氧基、羟基、硝基;R2选自氢、卤素、C1‑8烷基、C1‑8烷氧基、卤代C1‑8烷基、羧基;R1、R2取代位置选自任意位置的单取代、相同或不同基团的多取代。本发明的4‑肉桂基‑3‑羟基吡咯酮类化合物具有显著的促进胰岛β细胞分泌和合成胰岛素的作用,以及改善口服葡萄糖耐量和胰岛素敏感性的效果,可用于制备新型的治疗和/或预防糖尿病的药物。
Description
技术领域
本发明属于糖尿病治疗药物技术领域,具体涉及4-肉桂基-3-羟基吡咯酮类化合物在制备治疗糖尿病药物中的应用。
背景技术
糖尿病属于人类重大慢性非传染性疾病,严重威胁人类健康。正在临床应用的抗糖尿病药物多数以改善症状为主,无法彻底治愈该疾病。因此,亟需研发新作用机制和新结构类型的抗糖尿病药物。
最新研究表明,选择性地抑制组蛋白去乙酰化酶亚型3(HDAC3)可以保护胰岛β细胞和促进胰岛素分泌,从而有效降低糖尿病大鼠的血糖水平,且不影响人源巨核细胞的正常分化,可减小HDACs非选择性抑制引起的血小板减少的风险(Chou,D.H.;et al.ChemBiol 2012; Wagner,F.F.;et al.,ACS Chem Biol 2016;Lundh,M.;et al,DiabetesObes.Metab.,2015.)。因此, HDAC3可以作为抗糖尿病药物的潜在靶标。HDAC3的催化活性受到共阻遏蛋白NCoR或 SMRT的调控,其共阻遏蛋白不同于其它亚型,靶向HDAC3/NCoR复合物可能是选择性抑制 HDAC3的新策略(Watson,P.J.;et al.,Nature,2012)。
发明内容
本发明的目的是为了克服国内外市场上尚无HDAC3/NCoR靶向的抗糖尿病药物的不足,提供4-肉桂基-3-羟基吡咯酮类化合物在制备治疗糖尿病药物中的应用。
本发明提供如下技术方案:
第一方面,本发明提供了如式(1)所示的化合物或其药学上可接受的盐在制备治疗和/或预防糖尿病药物中的应用。
其中:
R1选自氢、卤素、C1-8烷氧基、羟基、硝基;
R2选自氢、卤素、C1-8烷基、C1-8烷氧基、卤代C1-8烷基、羧基;
R1、R2取代位置选自任意位置的单取代、相同或不同基团的多取代。
优选地,所述卤素选自氟、氯、溴、碘;所述C1-8烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、直链或含支链的戊氧基、直链或含支链的己氧基、直链或含支链的庚氧基、直链或含支链的辛氧基;所述C1-8烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、直链或含支链的戊基、直链或含支链的己基、直链或含支链的庚基、直链或含支链的辛基;所述卤代代表任意取代位置的单卤代、相同或不同卤素原子的多卤代。
进一步地,本发明所述的化合物为:
XJ0240:4-肉桂基-3-羟基-5-(3-甲氧基苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0241:4-肉桂基-3-羟基-5-苯基-1-(4-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0242:4-肉桂基-3-羟基-5-(4-甲氧基苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0243:4-肉桂基-3-羟基-5-(4-甲氧基苯基)-1-(4-甲苯基)-1H-吡咯-2(5H)-酮
XJ0244:4-肉桂基-3-羟基-5-(4-羟基-3-甲氧基苯基)-1-(4-乙氧基苯基)-1H-吡咯-2(5H)-酮
XJ0245:4-肉桂基-3-羟基-5-(4-氯苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0246:4-肉桂基-3-羟基-5-(2-氟苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0247:4-肉桂基-3-羟基-5-(2,4-二甲氧基苯基)-1-(4-乙氧基苯基)-1H-吡咯-2(5H)-酮
XJ0248:4-肉桂基-3-羟基-5-(4-羟基-3-甲氧基苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0249:4-肉桂基-3-羟基-5-(2-氟苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0250:4-肉桂基-3-羟基-5-(2,4-二甲氧基苯基)-1-(3-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0251:4-肉桂基-3-羟基-5-(4-氯苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0252:4-肉桂基-3-羟基-5-(2-硝基苯基)-1-(3-三氟甲基苯基)-1H-吡咯-2(5H)-酮
XJ0253:4-肉桂基-3-羟基-5-(4-溴苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0254:4-肉桂基-3-羟基-5-(4-氟苯基)-1-(3-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0255:4-肉桂基-3-羟基-5-(3,4-二甲氧基苯基)-1-(3-三氟甲基苯基)-1H-吡咯-2(5H)-酮
XJ0256:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0257:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0258:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0259:4-肉桂基-3-羟基-5-(4-羟基-3-甲氧基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0260:4-肉桂基-3-羟基-5-(3-氟苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0261:4-肉桂基-3-羟基-5-(4-溴苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0262:4-肉桂基-3-羟基-5-(4-氟苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0263:4-肉桂基-3-羟基-5-(2-硝基苯基)-1-(4-乙氧基苯基)-1H-吡咯-2(5H)-酮
XJ0264:4-肉桂基-3-羟基-5-(2-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0265:4-肉桂基-3-羟基-5-(2-氟苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0266:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0267:4-肉桂基-3-羟基-5-(4-硝基苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0268:4-肉桂基-3-羟基-5-(4-氯苯基)-1-(2-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0269:4-肉桂基-3-羟基-5-(4-硝基苯基)-1-(4-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0270:4-肉桂基-3-羟基-5-(4-溴苯基)-1-(2-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0271:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(3-三氟甲基苯基)-1H-吡咯-2(5H)-酮
XJ0272:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(2-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0273:4-肉桂基-3-羟基-5-(4-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮。
作为优选,本发明所述的治疗和/或预防糖尿病药物中的应用是通过抑制HDAC3/NCoR产生的,促进胰岛β细胞分泌和合成胰岛素的作用,以及改善口服葡萄糖耐量和胰岛素敏感性的效果。
第二方面,本发明提供了一种抗糖尿病药物组合物在制备治疗和/或预防糖尿病药物中的应用,该药物组合物含有上述4-肉桂基-3-羟基吡咯酮类化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。
进一步地,所述载体包括药学领域常规的赋形剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
作为优选,该药物给药剂型为注射剂、片剂、丸剂、胶囊、悬浮剂、乳剂或软膏,给药途径选自静脉或肌肉注射、口服、经皮给药、粘膜给药、直肠给药、阴道给药等。
与现有技术相比,本发明具有如下有益效果:
本发明所述的4-肉桂基-3-羟基吡咯酮类化合物靶向HDAC3/NCoR,是具有全新的作用机制抗糖尿病药物,体内外实验已证实该系列化合物可通过促进胰岛素分泌和合成,显著改善口服葡萄糖耐量和胰岛素敏感性。截至目前,国内外均未报道过相同作用机制的抗糖尿病药物,而且该结构类型不同于临床用抗糖尿病药物,对该结构类型深入研究将有望发现国际首创新药的糖尿病治疗药物。
附图说明
图1.MIN6细胞的胰岛素分泌及合成的实验结果。A)细胞胰岛素分泌水平;B)细胞内胰岛素含量。*p<0.05,**p<0.01,***p<0.001,vs.Vehicle组。
图2.糖尿病小鼠口服葡萄糖耐量(OGTT)和胰岛素耐量实验(ITT)结果。A)OGTT血糖值;B)OGTT血糖曲线下面积(AUC);C)ITT血糖值;D)ITT血糖曲线下面积(AUC)。 *p<0.05,**p<0.01,***p<0.001,vs.Con组。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但实施例仅用于说明本发明,而不是对本发明进行限制。实施例中所用实验方法如无特殊说明,均为常规方法;所使用的材料、试剂等如无特殊说明,为可从商业途径得到的试剂和材料。
一、化合物的获取
实施例1.化合物XJ0240-XJ0245的获取
化合物可从Compound Handling B.V.(Trade name:Specs)购买获得,公司地址为Bleiswijkseweg 55,2712PB Zoetermeer,The Netherlands,网购地址:https://www.specs.net/。
实施例2.化合物XJ2046-XJ0273的获取
化合物可从ChemDiv Inc.购买获得,公司地址为12760High Bluff Drive,Suite370San Diego, CA 92130 USA。网购地址:https://www.chemdiv.com/。
二、化合物的生物活性评价
实验例1.HDAC3/NCoR1酶抑制活性测定
1.实验方法
采用Enzo公司的HDAC3/NCoR1 Fluorometric Drug Discovery Kit测定酶抑制活性。反应在96孔板中进行。以Assay BufferⅡ稀释化合物至5×CFinal样品缓冲液,溶媒DMSO以相同体积加入BufferⅡ作为阴性对照。分别在各孔中加入25μL Assay BufferⅡ(空白对照)、或10μL 的阴性对照、或样品缓冲液(阳性对照TSA、或待测化合物);以Assay BufferⅡ稀释酶重组复合体HDAC3/NCoR1至3.3×CFinal酶工作液,加入到各孔中(15μL/孔,空白对照除外);以 Assay Buffer稀释底物FLUOR DE-SIRT1至2×CFinal底物工作液,并预热到37℃,向所有孔中加入25μL预热好的底物工作液,充分混匀后启动反应,37℃,孵育15~20min;然后立即向反应体系中加入50μL含有2μM TSA的DeveloperⅡ以终止反应,于室温孵育30-40 min,360/460nm测定OD值。
2.代表性化合物在10μM浓度下对HDAC3/NCoR1的抑制率、IC50见表1。
表1:代表性化合物对HDAC3/NCoR1的酶抑制活性。注:一般本领域技术人员认为在10μM 浓度下,化合物抑制率高于18%即为有效。
实验例2.体外药效学评价:化合物XJ0253对胰岛β细胞株MIN6细胞的胰岛素分泌和合成的作用。
1.胰岛细胞及培养
MIN6细胞,由南京医科大学韩晓课题组赠送。细胞复苏后接种于T25细胞瓶中,培养基为DMEM(高糖),于37℃、5%CO2培养箱中培养。待细胞生长至汇合度为80%左右时,消化细胞至单细胞混悬液,细胞计数,细胞活力在80%以上,接种于96孔板中,5×104细胞/100 μl/孔,培养24h后用于实验。
2.葡萄糖刺激胰岛素分泌实验
培养24h的MIN6细胞分别加入含有0.1%DMSO(阴性对照Vehicle)、10μM的XJ0253、1μM的RGFP966(阳性对照)的培养基继续培养24h。去除培养基,用含有2.8mM葡萄糖的Kreb’s缓冲液饥饿细胞1h。随后分别用含有2.8mM或16.8mM葡萄糖的Kreb’s缓冲液(100 μl/孔)培养细胞1h,收取上清检测细胞分泌的胰岛素含量。同时用RIPA裂解液(C1053,普利莱,北京)处理每孔细胞,用于蛋白定量以及细胞内胰岛素含量检测。采用小鼠胰岛素 ELISA检测试剂盒(Alpco,REF#80-INSMSU,USA)检测胰岛素含量,采用BCA蛋白定量试剂盒(P1513,普利莱,北京)检测每孔细胞蛋白量。
3.实验结果见见表2和图1
与阴性对照组(Vehicle)相比,在葡萄糖浓度为2.8mM和16.8mM条件下,XJ0253均明显促进MIN6细胞的胰岛素分泌。同时,XJ0253明显增加胰岛MIN6细胞内的胰岛素含量,提示XJ0253可促进细胞的胰岛素合成。
表2 MIN6细胞的胰岛素分泌及合成的实验结果。
*p<0.05,**p<0.01,***p<0.001,vs.Vehicle组。
实验例3.体内药效学评价:化合物XJ0253对糖尿病模型STZ/HFD-C57BL/6J小鼠葡萄糖耐量和胰岛素敏感性的作用。
1.糖尿病模型HFD/STZ-C57小鼠模型的建立
C57BL/6J小鼠(8周,雄性)购自华阜康生物科技有限公司,在中国医学科学院药物研究所SPF级动物房适应性喂养4天后,腹腔注射链脲霉素(streptozotocin,STZ)(50mg/kg)两次,随后给予高脂饲料(60%脂肪)喂养6周,检测小鼠空腹血糖,糖负荷(葡萄糖2.0g/kg灌胃)后30min的血糖和体重,筛选出糖负荷后30min血糖值在180mg/dl以上的小鼠,并参考体重随机分为辅型剂组(Con)和给药组(XJ0253)。同时,其他小鼠腹腔注射(柠檬酸缓冲液, 0.1ml/10g体重)两次,随后用正常饲料喂养,作为正常对照组(Nor)。
2.实验方法
给药组小鼠腹腔注射XJ0253(50mg/kg,qd),辅型剂组(Con)和正常对照组(Nor)小鼠腹腔注射0.5%CMC(0.1ml/10g体重)。分别于给药11天和18天进行口服葡萄糖耐量实验(OGTT)和胰岛素耐量实验(ITT)。
3.实验结果见见表3、表4和图2
相比于正常对照组(Nor),糖尿病模型小鼠(Con)口服葡萄糖耐量明显受损,表现为胰岛素抵抗。而XJ0253可明显改善糖尿病模型小鼠的口服葡萄糖耐量(表3、图2A-B)和胰岛素敏感性(表4、图2C-D),血糖曲线下面积(AUC)分别下降20.7%和19.4%。
表3糖尿病小鼠口服葡萄糖耐量(OGTT)结果。
*p<0.05,**p<0.01,***p<0.001,vs.Con组。
表4糖尿病小鼠胰岛素耐量实验(ITT)结果。
*p<0.05,**p<0.01,***p<0.001,vs.Con组。
Claims (7)
2.根据权利要求1所述的应用,其特征在于,
所述卤素选自氟、氯、溴、碘;
所述C1-8烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、直链或含支链的戊氧基、直链或含支链的己氧基、直链或含支链的庚氧基、直链或含支链的辛氧基;
所述C1-8烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、直链或含支链的戊基、直链或含支链的己基、直链或含支链的庚基、直链或含支链的辛基;
所述卤代代表任意取代位置的单卤代、相同或不同卤素原子的多卤代。
3.根据权利要求1所示的应用,其特征在于,所述的化合物选自如下群组:
XJ0240:4-肉桂基-3-羟基-5-(3-甲氧基苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0241:4-肉桂基-3-羟基-5-苯基-1-(4-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0242:4-肉桂基-3-羟基-5-(4-甲氧基苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0243:4-肉桂基-3-羟基-5-(4-甲氧基苯基)-1-(4-甲苯基)-1H-吡咯-2(5H)-酮
XJ0244:4-肉桂基-3-羟基-5-(4-羟基-3-甲氧基苯基)-1-(4-乙氧基苯基)-1H-吡咯-2(5H)-酮
XJ0245:4-肉桂基-3-羟基-5-(4-氯苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0246:4-肉桂基-3-羟基-5-(2-氟苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0247:4-肉桂基-3-羟基-5-(2,4-二甲氧基苯基)-1-(4-乙氧基苯基)-1H-吡咯-2(5H)-酮
XJ0248:4-肉桂基-3-羟基-5-(4-羟基-3-甲氧基苯基)-1-苯基-1H-吡咯-2(5H)-酮
XJ0249:4-肉桂基-3-羟基-5-(2-氟苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0250:4-肉桂基-3-羟基-5-(2,4-二甲氧基苯基)-1-(3-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0251:4-肉桂基-3-羟基-5-(4-氯苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0252:4-肉桂基-3-羟基-5-(2-硝基苯基)-1-(3-三氟甲基苯基)-1H-吡咯-2(5H)-酮
XJ0253:4-肉桂基-3-羟基-5-(4-溴苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0254:4-肉桂基-3-羟基-5-(4-氟苯基)-1-(3-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0255:4-肉桂基-3-羟基-5-(3,4-二甲氧基苯基)-1-(3-三氟甲基苯基)-1H-吡咯-2(5H)-酮
XJ0256:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0257:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0258:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0259:4-肉桂基-3-羟基-5-(4-羟基-3-甲氧基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0260:4-肉桂基-3-羟基-5-(3-氟苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0261:4-肉桂基-3-羟基-5-(4-溴苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0262:4-肉桂基-3-羟基-5-(4-氟苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0263:4-肉桂基-3-羟基-5-(2-硝基苯基)-1-(4-乙氧基苯基)-1H-吡咯-2(5H)-酮
XJ0264:4-肉桂基-3-羟基-5-(2-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮
XJ0265:4-肉桂基-3-羟基-5-(2-氟苯基)-1-(3-羧基苯基)-1H-吡咯-2(5H)-酮
XJ0266:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0267:4-肉桂基-3-羟基-5-(4-硝基苯基)-1-(4-甲氧基苯基)-1H-吡咯-2(5H)-酮
XJ0268:4-肉桂基-3-羟基-5-(4-氯苯基)-1-(2-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0269:4-肉桂基-3-羟基-5-(4-硝基苯基)-1-(4-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0270:4-肉桂基-3-羟基-5-(4-溴苯基)-1-(2-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0271:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(3-三氟甲基苯基)-1H-吡咯-2(5H)-酮
XJ0272:4-肉桂基-3-羟基-5-(3-硝基苯基)-1-(2-甲基苯基)-1H-吡咯-2(5H)-酮
XJ0273:4-肉桂基-3-羟基-5-(4-硝基苯基)-1-(4-碘苯基)-1H-吡咯-2(5H)-酮。
4.一种药物组合物在制备治疗和/或预防糖尿病药物中的应用,其特征在于,所述的药物组合物包括权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂。
5.根据权利要求4的应用,其特征在于,所述的药物组合物选自注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂。
6.根据权利要求1的应用,其特征在于,所述治疗和/或预防糖尿病药物是通过抑制HDAC3/NCoR产生的治疗效果。
7.根据权利要求6的应用,其特征在于,所述的治疗效果包括对胰岛β细胞分泌和合成胰岛素的促进作用,以及改善口服葡萄糖耐量和胰岛素敏感性。
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