本文選題：PPARs + 多靶點激動劑��； 參考：《天津醫(yī)科大學(xué)》2015年碩士論文

【摘要】：目的:過氧化物酶體增殖因子活化受體(peroxisome proliferators activated receptor,PPAR)是核受體家族成員之一,包括α、γ、δ三個亞型,與糖尿病、肥胖癥、脂質(zhì)異常等疾病的發(fā)生發(fā)展密切相關(guān)。噻唑烷二酮類PPARγ激動劑作為抗糖尿病藥物由于存在心臟安全性等副作用,已在臨床限制使用。選擇性的激動PPARγ亞型是產(chǎn)生這些副作用的主要原因。近年來,隨著糖尿病形成機(jī)理研究的不斷深入,多靶點協(xié)同作用的PPARα/γ雙重激動劑、PPARα/γ/δ共激動劑等已引起人們的廣泛關(guān)注。本論文利用計算機(jī)輔助設(shè)計先進(jìn)手段,設(shè)計并合成具有降糖、降脂協(xié)同作用的PPARs多靶點激動劑,以期避免現(xiàn)有噻唑烷二酮類藥物的副作用,為新型多靶點抗糖尿病藥物研發(fā)奠定基礎(chǔ)。方法:(1)以羅格列酮為先導(dǎo)物,采用骨架躍遷的策略對其極性頭部、中間鏈狀結(jié)構(gòu)和疏水尾部進(jìn)行結(jié)構(gòu)改造,建立了類似物分子庫。然后通過分子對接評價這些類似物與PPARα/γ/δ的結(jié)合情況,并且預(yù)測其ADMET性質(zhì),篩選出8個具有較好結(jié)合構(gòu)像和藥動學(xué)性質(zhì)的PPARα/γ/δ共激動劑。以原始配體為對照,對其中的代表化合物1進(jìn)行分子動力學(xué)模擬研究,結(jié)果表明化合物1能與靶點更穩(wěn)定的結(jié)合,從而為新型PPARs多靶點激動劑類降糖藥的研發(fā)提供了結(jié)構(gòu)參考。(2)借鑒苯氧基烷酸類PPARa激動劑和噻唑烷二酮類PPARγ激動劑的共同結(jié)構(gòu)特征,根據(jù)藥物化學(xué)的拼合原理,將苯氧基烷酸類藥物的極性頭部和噻唑烷二酮類藥物的疏水尾部整合在一個分子中,設(shè)計了具有協(xié)同增效作用的PPARα/γ/δ共激動劑,以期避免現(xiàn)有噻唑烷二酮類藥物的副作用。(3)以對苯二酚為原料,與2-溴-2-甲基丙二酸乙酯反應(yīng),生成單取代的中間體2-(4-羥基-苯氧基)-2-甲基-丙酸乙酯(WB-1-2)。該中間體進(jìn)一步與各種鹵化物反應(yīng),如苯丙基氯,2-氯苯乙酮,3-氯甲基吡啶鹽酸鹽,5-乙基-2氯乙基吡啶,N-氯乙基咔唑,N-氯丙基咔唑,N-氯乙基吲哚,N-氯乙基苯并咪唑,N-氯丙基苯并咪唑,生成各種酯類化合物,然后水解得到羧酸類目標(biāo)化合物。目標(biāo)化合物通過氫譜、碳譜及質(zhì)譜確認(rèn)結(jié)構(gòu)。結(jié)果:(1)本論文對羅格列酮進(jìn)行結(jié)構(gòu)改造,篩選出8個具有較好結(jié)合構(gòu)像和藥動學(xué)性質(zhì)的PPARα/γ/δ共激動劑。對其中的代表化合物1進(jìn)行了分子動力學(xué)模擬研究,結(jié)果表明化合物1能與靶點更穩(wěn)定的結(jié)合。(2)本論文將苯氧基烷酸類藥物的極性頭部和噻唑烷二酮類藥物的疏水尾部整合在一個分子中,設(shè)計了具有協(xié)同增效作用的PPARα/γ/δ共激動劑。對其中部分化合物進(jìn)行了化學(xué)合成,得到了18個目標(biāo)化合物并確證其結(jié)構(gòu)。結(jié)論:本論文以PPARα/γ/δ為藥物作用靶標(biāo),設(shè)計了具有多靶點作用的PPARα/γ/δ激動劑。對代表性化合物進(jìn)行合成,得到18個目標(biāo)化合物,其化學(xué)結(jié)構(gòu)經(jīng)過氫譜、碳譜和質(zhì)譜確證。本論文的工作為發(fā)現(xiàn)具有深入研究價值的降糖藥物先導(dǎo)物奠定了基礎(chǔ)。
[Abstract]:Objective: peroxisome proliferator factor-activated receptor (peroxisome proliferators activated) is a member of nuclear receptor family, including 偽, 緯, 未 subtypes, which is closely related to the occurrence and development of diabetes, obesity, lipid abnormalities and other diseases. Thiazolidinedione PPAR 緯 agonists have been restricted in clinical use as antidiabetic drugs due to cardiac safety and other side effects. Selective activation of PPAR 緯 subtypes is the main cause of these side effects. In recent years, with the development of the mechanism of diabetes mellitus, the multi-target synergistic PPAR 偽 / 緯 dual agonist, PPAR 偽 / 緯 / 未 co-agonist, has attracted much attention. In this paper, we designed and synthesized PPARs multi-target agonists with the synergistic effect of hypoglycemic and lipid-lowering by computer aided design, in order to avoid the side effects of the existing thiazolidinedione drugs. To lay a foundation for the research and development of new multi-target anti-diabetic drugs. Methods: (1) with rosiglitazone as the leader, the structure of polar head, intermediate chain structure and hydrophobic tail were modified by the strategy of skeleton transition, and the analogous molecular library was established. Then the binding of these analogues to PPAR 偽 / 緯 / 未 was evaluated by molecular docking, and ADMET properties were predicted. Eight PPAR 偽 / 緯 / 未 co-agonists with good conformation and pharmacokinetic properties were selected. The molecular dynamics simulation of the representative compound 1 was carried out by using the original ligand as a control. The results showed that compound 1 could bind to the target more stably. It provides a structural reference for the research and development of novel PPARs multitarget agonists. (2) based on the common structural characteristics of phenoxyalkanoic acid PPARa agonists and thiazolidinedione PPAR 緯 agonists, according to the principle of pharmacochemistry, The polar head of phenoxy alkanoic acid and the hydrophobic tail of thiazolidinedione were integrated into one molecule, and a synergistic PPAR 偽 / 緯 / 未 co-agonist was designed. In order to avoid the side effects of the existing thiazolidinediketones. (3) the monosubstituted intermediate 2- (4-hydroxy-phenoxy) -2-methyl-propionate (WB-1-2) was synthesized by the reaction of hydroquinone with ethyl 2-bromo-2-methylmalonate. The intermediate further reacts with various halides, For example, phenylpropyl chloro 2-chloro-acetophenone 3-chloromethylpyridine hydrochloride, 5-ethyl 2-chloroethyl pyridine, N-chloropropyl carbazole, N-chloropropyl indole-N-chloroethyl benzimidazole, N-chloropropyl benzimidazole, The carboxylic acid target compounds are then hydrolyzed. The target compounds were identified by hydrogen, carbon and mass spectra. Results: (1) eight PPAR 偽 / 緯 / 未 co-agonists with good conformational and pharmacokinetic properties were screened by structural modification of rosiglitazone. Molecular dynamics simulation of one of the representative compounds 1 was carried out. The results showed that compound 1 could bind to the target more stably. (2) in this paper, the polar head of phenoxy alkanoic acid and the hydrophobic tail of thiazolidinedione were integrated into one molecule, and a synergistic PPAR 偽 / 緯 / 未 co-agonist was designed. Some of the compounds were chemically synthesized and 18 target compounds were obtained and their structures were confirmed. Conclusion: in this thesis, PPAR 偽 / 緯 / 未 agonists with multiple targets were designed. Eighteen target compounds were synthesized and their chemical structures were confirmed by hydrogen spectrum, carbon spectrum and mass spectrometry. The work of this paper lays a foundation for the discovery of hypoglycemic drug precursors.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R91;R914.5

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 Michael S Kostapanos;Anastazia Kei;Moses S Elisaf;;Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease[J];World Journal of Hepatology;2013年09期

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本文編號：2111796