本文選題：乙酰膽堿酯酶　切入點(diǎn)：β淀粉樣肽　出處：《復(fù)旦大學(xué)》2014年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：阿爾茨海默病是一種以進(jìn)行性記憶減退、智力衰退、語(yǔ)言行為障礙甚至意識(shí)喪失為主要癥狀的神經(jīng)退行性疾病。阿爾茨海默病的具體發(fā)病機(jī)制還未被完全研究清楚,主要認(rèn)為“β淀粉樣肽(Aβ)沉積”和“tau蛋白的異常磷酸化”是導(dǎo)致阿爾茨海默病發(fā)病的兩個(gè)重要機(jī)制,而“膽堿能神經(jīng)損傷”是導(dǎo)致阿爾茨海默病患者認(rèn)知和行為障礙的主要病理因素�，F(xiàn)在用于阿爾茨海默病治療的藥物大多數(shù)都是乙酰膽堿酯酶(AChE)抑制劑。使用AChE抑制劑只能改善阿爾茨海默病患者的癥狀,并不能徹底治愈或改變阿爾茨海默病的病理過(guò)程。目前AChE抑制劑的研究主要集中于尋找更加安全或具有多重作用的AChE抑制劑。本文基于已發(fā)現(xiàn)的雙位點(diǎn)AChE抑制劑XQ509,針對(duì)XQ509口服生物利用度差和抑制郵聚集活性相對(duì)較低的缺點(diǎn),對(duì)XQ509復(fù)合物晶體結(jié)構(gòu)信息進(jìn)行分析,并結(jié)合計(jì)算機(jī)輔助藥物設(shè)計(jì)軟件,設(shè)計(jì)并合成了三個(gè)系列的目標(biāo)化合物。第一系列化合物以改善口服生物利用度為目標(biāo),用雜原子或極性基團(tuán)取代-Q509的全碳連接鏈。第二、第三系列化合物以提高抑制Aβ聚集活性為目標(biāo),用不同長(zhǎng)度的連接鏈連接(-)-美普他酚和多奈哌齊茚酮結(jié)構(gòu)或鄰苯二甲酰亞胺結(jié)構(gòu)。對(duì)三個(gè)系列目標(biāo)化合物進(jìn)行AChE抑制活性測(cè)試。第一系列目標(biāo)化合物測(cè)試結(jié)果顯示雜原子或極性基團(tuán)取代連接鏈對(duì)化合物的活性有較大的影響。這可能是因?yàn)檫B接鏈需要有一定的柔性來(lái)達(dá)到最優(yōu)的結(jié)合構(gòu)象,在某些位置增加雜原子可能導(dǎo)致化合物分子不能扭轉(zhuǎn)至最優(yōu)的構(gòu)象,從而造成化合物抑制活性的下降。這一系列活性最好的化合物(1b、1e)的IC50分別達(dá)到4.4 nM和4.3 nM,與化合物XQ509 (IC505.7nM)相當(dāng)。第二系列茚酮類(lèi)目標(biāo)化合物測(cè)試結(jié)果顯示連接鏈長(zhǎng)度與活性密切相關(guān),最適長(zhǎng)度為5-6碳。這一系列活性最好的化合物(2d、2e)的IC50分別達(dá)到12 nM和14 nM,均優(yōu)于多奈哌齊(IC5055nM)。第三系列目標(biāo)化合物測(cè)試結(jié)果顯示鄰苯二甲酰亞胺類(lèi)化合物的活性相對(duì)較差。對(duì)AChE抑制活性較高的化合物(1b、1e、2d、2e)進(jìn)行初步的AChE誘導(dǎo)Aβ聚集抑制活性試驗(yàn),結(jié)果發(fā)現(xiàn)這些化合物抗Aβ聚集的活性相較XQ509并未提高。進(jìn)一步分子對(duì)接和構(gòu)象分析發(fā)現(xiàn)在外周陰離子位點(diǎn)的結(jié)合差異明顯,且不牢固。其中活性最高的化合物1b在50μM濃度下對(duì)Aβ聚集的抑制率為44.8%,低于XQ509(抑制率58.4%)。目標(biāo)化合物經(jīng)計(jì)算機(jī)輔助藥物設(shè)計(jì)軟件ADME/T性質(zhì)預(yù)測(cè),預(yù)示水溶解度、口服吸收以及血腦屏障透過(guò)率均較好。大鼠體內(nèi)口服生物利用度初步評(píng)價(jià)結(jié)果表明,化合物(1b、1e、2d、2e)的口服吸收并沒(méi)有得到提高,甚至出現(xiàn)下降,特別是茚酮類(lèi)化合物2d。其中口服生物利用度最高的化合物1b,絕對(duì)生物利用度為5.54%,略低于XQ509(F=8.40%)。通過(guò)進(jìn)一步的測(cè)試發(fā)現(xiàn)此類(lèi)化合物的肝微粒體代謝穩(wěn)定性較差,可能是導(dǎo)致口服生物利用度較差的另外一個(gè)因素。在所有目標(biāo)化合物中1b具有與XQS09最接近的體外AChE抑制活性、抗Aβ聚集活性和代謝穩(wěn)定性,口服生物利用度較XQ509差別不大,極性羥基的引入可能對(duì)藥物的組織分布有改善作用,值得進(jìn)一步研究。
[Abstract]:Alzheimer's disease is a progressive memory loss, mental decline, language behavior disorders and even loss of consciousness as the main symptoms of the neurodegenerative diseases. The pathogenesis of Alzheimer's disease has not been fully understood, mainly that beta amyloid (A beta) deposition and abnormal phosphorylation of tau protein "is the two important mechanisms of the pathogenesis of Alzheimer's disease, and cholinergic nerve injury is the main pathological disease and cognitive and behavior disorders of Alzheimer's factors. Now the majority of drugs for treatment of Alzheimer's disease are acetylcholinesterase (AChE) inhibitors. AChE inhibitors can improve the symptoms of Alzheimer's disease patients, and pathological process can not be completely cured or change of Alzheimer's disease. At present, the study of AChE inhibitors mainly focused on looking for safer or with multiple AChE inhibitor. This paper has found two locus AChE inhibitors based on XQ509 XQ509 for poor oral bioavailability and inhibit post aggregation activity is relatively low the shortcomings of complex structure of XQ509 information analysis, and combined with the computer aided drug design software design and the target compounds synthesized three series of the first. A series of compounds to improve oral bioavailability as the goal, with heteroatom or polar groups substituted carbon chain connecting -Q509. Second, third series of compounds to improve the inhibition of A beta aggregation activity as the goal, with different length of the connecting link (-) - meptazinol and donepezil indone structure or phthalate two methyl imide structure. The AChE inhibitory activity of three series of target compounds. The first series of target compounds test results show that the heteroatom or polar groups substituted for connecting chain compounds Has great influence on the activity. This may be because the connection chain needs to have certain flexibility to achieve optimal binding conformation, increasing heteroatoms in certain positions may lead to the optimal conformation compounds can not be reversed, resulting in decrease in compound inhibitory activity. Compounds of this series of the best activity (1b, 1e) IC50 respectively. Up to 4.4 nM and 4.3 nM, and compound XQ509 (IC505.7nM). The second series of indenone compounds test results show that the connection chain length and activity is closely related to the optimal length of 5-6 carbon compounds. This series of the best activity (2D, 2e) IC50 were respectively 12 nM and 14 nM were better than that of donepezil (IC5055nM). Third compounds of series test results show that the adjacent benzene two phthalimide compounds activity is relatively poor. Higher inhibitory activity of compounds AChE (1b, 1e, 2D, 2e) of AChE induced by A Inhibitory activity test results showed that anti A beta aggregation, these compounds beta aggregation activity compared with XQ509 did not improve. Further molecular docking and conformational analysis found in the peripheral anionic binding sites significantly different, and not strong. The compounds that inhibit the activity of 1b is the highest aggregation of A beta in 50 M concentration rate is 44.8%. Less than XQ509 (inhibition rate 58.4%). Prediction of target compounds by computer aided drug design software ADME/T properties, water solubility prediction, oral absorption and blood brain barrier permeability in rats. Good oral bioavailability of preliminary evaluation results showed that the compounds (1b, 1e, 2D, 2e) of the oral absorption and no improvement, or even decline, especially the indenone compound 2D. the oral bioavailability of the highest compound 1b, absolute bioavailability was 5.54%, slightly lower than XQ509 (F=8.40%). Through further testing found this Liver microsomal metabolism stability of compounds may lead to poor oral bioavailability is another factor of poor. In all the target compounds in 1b is the most close to XQS09 in vitro AChE inhibitory activity, anti A beta aggregation activity and metabolic stability, oral bioavailability is XQ509 little difference, introducing the polar hydroxyl group may the drug distribution effect, it is worthy of further study.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R91

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本文編號(hào)：1644727