本文選題：TGR5 + 腸道靶向藥物��； 參考：《中國科學(xué)院大學(xué)(中國科學(xué)院上海藥物研究所)》2017年博士論文

【摘要】：腸道靶向藥物是一類口服后選擇性地在腸道發(fā)揮藥效的藥物。這些化合物具有血漿暴露量低,腸道組織中濃度高的特點,因此腸道靶向藥物有可能避免高系統(tǒng)暴露量相關(guān)的副作用。這種設(shè)計策略被廣泛運用到糖尿病、肥胖癥、感染性疾病和炎癥等疾病的藥物開發(fā)中。TGR5是細胞膜表面的GPCR,其內(nèi)源性配體是膽汁酸。TGR5受體參與了血糖穩(wěn)態(tài)、免疫系統(tǒng)、肝膽功能、胃腸道功能等的調(diào)節(jié)。其中最主要且明確的是TGR5受體對于血糖穩(wěn)態(tài)的調(diào)節(jié)。腸道分泌細胞上TGR5的激動會促進GLP-1、GLP-2和PYY的分泌。GLP-1可以促進血糖依賴的胰島素釋放,抑制食欲,減緩胃排空等,從而維持血糖穩(wěn)態(tài)。GLP-2主要維系腸道的完整,促進腸道組織的生長。PYY發(fā)揮抑制食欲的作用。因此TGR5激動劑是潛在的抗糖尿病和腸道疾病的藥物。但TGR5受體在膽囊上的激動會導(dǎo)致膽汁排出受阻,膽囊體積增大。開發(fā)腸道靶向的TGR5激動劑有可能規(guī)避膽汁充盈的副作用。本文主要從軟藥策略出發(fā)進行腸道靶向TGR5激動劑的設(shè)計。軟藥是一類吸收后迅速被代謝失活的化合物。本文首先通過對高體外活性的B1結(jié)構(gòu)優(yōu)化,然后對化合物庫的整理,最終找到了酯類化合物B12a,其可在血漿中代謝成低活性的羧酸B13a。為了加快化合物血漿代謝速率,分別通過去除B12a苯并呋喃環(huán)上的氯原子,酯基位點更換成更高活性的酯、吡啶環(huán)位點的變換的方式最終得到了C1g,C1i等化合物,它們具有較好的體外活性和血漿代謝速率�？诜幋囼炛蠧1g,C1i在血漿、膽囊、膽汁中的濃度都極低。與之相對應(yīng)的是,無論是在ICR小鼠連續(xù)三天給藥還是db/db小鼠連續(xù)四天大劑量給藥試驗中,C1g,C1i都沒有表現(xiàn)出明顯的膽汁充盈副作用。系統(tǒng)的研究還表明化合物的血漿代謝速率越快,體內(nèi)暴露量越低,膽囊副作用越微弱。在ICR小鼠單次口服OGTT試驗中,C1g,C1i都表現(xiàn)出了顯著的降糖活性。同時這系列化合物在配樣所用的0.25%的CMC-Na水溶液中和p H 1.2的模擬胃液中的穩(wěn)定性能滿足體內(nèi)試驗的需求。以上試驗表明了軟藥策略用于腸道靶向TGR5激動劑的可行性。但C1g,C1i還存在一些缺陷,一是C1g與C1i的Caco-2細胞滲透性還并不低(Papp約為1×10-6 cm/s);二是體內(nèi)藥代試驗中,兩個化合物在腸道組織中的濃度還不夠高。從提高化合物極性的角度出發(fā)進行改造,希望降低這類軟藥化合物的細胞滲透性,同時增加化合物在腸道組織中的濃度。分別在酯基位點、四氫喹喔啉位點、中間吡啶環(huán)位點修飾,引入大極性的基團。最終發(fā)現(xiàn)吡啶氮原子修飾成季銨鹽的D5g具有較好的h TGR5體外活性,較快的血漿代謝速率,同時Caco-2細胞滲透性極低,Papp僅為0.01×10-6 cm/s。但D5g及類似化合物的體外活性都存在著顯著的種屬差異,這種種屬差異部分來源于苯并呋喃環(huán)。因此設(shè)計將C1g,C1i類似物和D5g類似物的苯并呋喃環(huán)開環(huán),分別得到D7j,D7l和D9m。D7j,D7l與C1g,C1i活性接近,而血漿中水解速率更快。而D9m的體外活性的種屬差異有所緩解,h TGR5 EC50為84 n M,而m TGR5 EC50為499 n M,兩者差異僅5.9倍。其m TGR5活性是吡啶季銨鹽類里唯一活性能達到幾百n M水平的化合物。另一方面,降低化合物的水溶性也能顯著降低化合物的吸收。鏈型結(jié)構(gòu)并環(huán)有可能增加其晶格能,從而降低水溶性。同時并環(huán)策略還能增加化合物的新穎性,有利于后期的專利保護。本文以A21a和B1為基礎(chǔ),通過不同位置的并環(huán)和最初的構(gòu)效關(guān)系優(yōu)化,初步找到了取代苯并含氮雜環(huán)類化合物具有中等的體外活性,其中最優(yōu)的化合物為E5c。
[Abstract]:Intestinal targeting drugs are a class of drugs that are selectively used in the intestinal tract after oral administration. These compounds have low levels of plasma exposure and high concentrations in the intestinal tissue. Therefore, intestinal targeting drugs may avoid high systemic exposure related side effects. This design strategy is widely used in diabetes, obesity, infectious diseases. In the development of diseases such as disease and inflammation,.TGR5 is the GPCR on the surface of the cell membrane, and its endogenous ligand is that the bile acid.TGR5 receptor participates in the regulation of blood glucose homeostasis, immune system, liver and bile function, gastrointestinal function and so on. The most important and explicit is the regulation of the TGR5 receptor for the homeostasis of blood glucose. The excitations of TGR5 on the intestinal secretory cells will promote G The secretion of.GLP-1 from LP-1, GLP-2 and PYY can promote insulin release of Blood Glucose dependent, inhibit appetite, slow down gastric emptying, and maintain the integrity of the blood glucose homeostasis.GLP-2 to maintain the integrity of the intestinal tract and promote the growth of intestinal tissue by.PYY to inhibit the appetite. Therefore, TGR5 agonists are potential drugs for anti diabetes and intestinal diseases. But TGR5 The excitant of the receptor on the gallbladder leads to the obstruction of the bile and the enlargement of the gallbladder. The development of the TGR5 agonist to target the intestinal tract may avoid the side effects of the bile filling. This article mainly designs the intestinal target TGR5 agonist based on the soft drug strategy. The B1 structure of high in vitro activity was optimized and then the ester compound B12a was finally found, which could be metabolized in plasma into a low active carboxylic acid B13a. in order to accelerate the plasma metabolic rate of the compound. By removing the chlorine atoms from the B12a benzofuran ring, the ester base site was replaced to the higher active ester, and the pyridine ring position was changed. C1g, C1i and other compounds have good extracorporeal and plasma metabolic rates. In oral administration, C1g, C1i in plasma, gallbladder, and bile are very low. In contrast, it is in ICR mice for three days or in db/db mice for four days in a large dose trial, C1g, C1i did not show obvious bile filling side effects. The systematic study also showed that the faster the plasma metabolism rate of the compound, the lower the exposure in the body, the weaker the side effect of the gallbladder. In the single oral OGTT test of ICR mice, C1g and C1i showed significant hypoglycemic activity. And the series of compounds were 0.25% of CMC used in the matching of samples. The stability in the simulated gastric juice of the -Na water solution and P H 1.2 meets the needs of the body test. The above test shows the feasibility of using the soft drug strategy to target the intestinal TGR5 agonist. But C1g, C1i still has some defects, one is that the Caco-2 cell permeability of C1g and C1i is not low (Papp is about 1 x 10-6 cm/s); two is in the drug test in vivo, The concentration of the two compounds in the intestinal tissue is not high enough. From the angle of improving the polarity of the compound, it is hoped to reduce the cell permeability of these soft compounds and increase the concentration of the compounds in the intestinal tissue. It was found that D5g of pyridine nitrogen atoms modified to quaternary ammonium salt had good in vitro activity of H TGR5, rapid plasma metabolic rate, and very low permeability of Caco-2 cells, Papp was only 0.01 x 10-6 cm/s., but the activity of D5g and similar compounds in vitro had significant differences in species genera, and this species was partly derived from benzofuran. Therefore, C1g, C1i analogues and D5g analogues were designed to ring the benzofuran ring of D5g analogues, and D7j, D7l and D9m.D7j, D7l and C1g, and C1i activity was close, and the rate of hydrolysis in plasma was faster. The difference in the activity of D9m in vitro was relieved, and the difference was only 5.9 times. The only activity of the pyridine quaternary ammonium salts can reach the level of several hundred N M. On the other hand, reducing the water solubility of the compound can also significantly reduce the absorption of the compound. The chain structure and ring may increase its lattice energy and reduce the water solubility. Meanwhile, the ring strategy can also increase the novelty of the compounds, which is beneficial to the patent protection in the later period. On the basis of A21a and B1, this paper preliminarily found that the substituted benzo and nitrogen heterocyclic compounds have medium extracorporeal activity through the optimization of the annulus and the initial structure-activity relationship, and the best compound is E5c..

【學(xué)位授予單位】：中國科學(xué)院大學(xué)(中國科學(xué)院上海藥物研究所)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R914;R96
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本文編號：1804172