本文關(guān)鍵詞：新型NNRTIs二芳基苯胺類和HIV成熟抑制劑Bevirimat雙靶點(diǎn)化合物的設(shè)計(jì)、合成、生物活性及體外代謝評(píng)價(jià)　出處：《中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院》2017年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 非核苷類逆轉(zhuǎn)錄酶抑制劑 Bevirimat 二芳基苯胺類 抗HIV病毒藥物

【摘要】：艾滋病(acquired immunodeficiency syndrome,AIDS)是由人類免疫缺陷病毒(human immunodeficiency virus,HIV)感染引起的疾病,也是當(dāng)前醫(yī)學(xué)界難以治愈的頑疾之一。2016年全球艾滋病統(tǒng)計(jì)數(shù)據(jù)估計(jì),2015年有3670萬人感染艾滋病毒。其中,200萬人是新增感染者,110萬人死于與艾滋病有關(guān)的疾病。盡管針對(duì)病毒生命的不同階段進(jìn)行抑制的被批準(zhǔn)上市的藥物已有30多種,但還沒有徹底治愈HIV感染的療法。臨床上使用的高效抗逆轉(zhuǎn)錄病毒療法能有效緩解患者的病情,極大的降低患者體內(nèi)的病毒載量,延長(zhǎng)患者壽命,但該療法并不能從根源上將患者體內(nèi)的HIV病毒清除,還存在明顯毒副作用,患者依從性較差,研究新型抗HIV藥物為臨床提供安全,經(jīng)濟(jì)用藥選擇變得尤為重要。本課題組前期研究發(fā)現(xiàn)兩類新結(jié)構(gòu)類型的非核苷類逆轉(zhuǎn)錄酶抑制劑(non-nucleoside reverse transcriptase inhibitors,NNRTIs)先導(dǎo)化合物:二芳基吡啶胺類(diarylpyridinamines,DAPAs)和二芳基苯胺類(diarylanilines,DAANs)化合物,它們對(duì)HIV野生型和多種耐藥型病毒均有較強(qiáng)抑制活性,與同類上市藥Riplivirine的活性相當(dāng),并能有效抑制其新生耐藥性病毒的復(fù)制。Bevirimat(BVM,3-O-(3′,3′-dimethylsuccinyl)betulinic acid)是第一個(gè)進(jìn)入臨床試驗(yàn)的成熟抑制劑。它干擾了CA-SP1(capsid-spacer protein 1)到CA(capsid)的加工,導(dǎo)致CA-SP1的積累并組裝釋放未成熟的HIV病毒,此病毒不具有感染能力,從而阻斷了HIV病毒的傳播。已通過IIa期臨床試驗(yàn),證明了其臨床療效和安全性。作為持續(xù)性研究,本課題意將高活性的二芳基苯胺類化合物與bevirimat經(jīng)適當(dāng)?shù)闹虚g體連接,合成雙靶點(diǎn)化合物,再對(duì)其進(jìn)行活性以及體外代謝性能的考察。以期發(fā)現(xiàn)高活性、體內(nèi)易代謝分離、可同時(shí)作用于不同靶點(diǎn)的雙靶點(diǎn)新型化合物,發(fā)揮1+12的協(xié)同抗HIV的作用和克服HIV藥物的耐藥性問題。本文對(duì)中間體和偶合方法進(jìn)行了探索,將不同類型的中間體連在DAAN母核B環(huán)的2-或4-位上,共計(jì)合成20個(gè)二芳基苯胺類衍生物,并對(duì)新合成的二芳基苯胺類衍生物進(jìn)行了抗HIV病毒活性和代謝穩(wěn)定性評(píng)價(jià),其中活性化合物16個(gè),經(jīng)活性及類藥性評(píng)價(jià)得構(gòu)效關(guān)系如下:1)在DAAN的B環(huán)4-位進(jìn)行連接側(cè)鏈,取代基R2較長(zhǎng)或者連接基團(tuán)極性增大,都會(huì)使活性降低;引入短鏈可以保持或者改善分子的抗HIV活性,在分子抗耐藥方面的表現(xiàn)短鏈優(yōu)于長(zhǎng)鏈。2)在人肝微粒體模型代謝穩(wěn)定性試驗(yàn)當(dāng)中,二芳基苯胺類化合物中B環(huán)2-位酰胺基取代的化合物比B環(huán)4-位酰胺取代的化合物更易不穩(wěn)定,且B環(huán)4-位酯鍵修飾要比酰胺鍵側(cè)鏈更不穩(wěn)定。3)在DAAN類中B環(huán)2-位氨基上連接脂肪鏈R1后,均會(huì)減弱DAAN母核的抗HIV活性,游離出氨基,抗HIV活性最好,這也與前其研究結(jié)論一致,此位點(diǎn)與K101的氨基酸殘基能產(chǎn)生作用,是抗HIV病毒的活性關(guān)鍵基團(tuán)。經(jīng)探索合成3個(gè)DAAN與BVM雙靶點(diǎn)偶合物,并沒有檢測(cè)到抗HIV活性,對(duì)中間體的嘗試還有待提高。由人肝微粒體代謝穩(wěn)定性試驗(yàn)可知,雙靶點(diǎn)化合物的代謝半衰期t1/2均明顯小于參比對(duì)照鹽酸普奈洛爾和TMC278,說明雙靶點(diǎn)化合物能夠在酶的參與下發(fā)生代謝。相對(duì)應(yīng)的DAAN中間體也進(jìn)行了代謝穩(wěn)定性考察,代謝半衰期t1/2分別為10.7 min,75.3 min,117.5 min。暗示在DAAN類的B-環(huán)2-位的氨基連接側(cè)鏈的長(zhǎng)度越長(zhǎng),越容易被代謝,可以指導(dǎo)中間體的進(jìn)一步探索。綜上所述,本課題經(jīng)探索合成了非核苷類逆轉(zhuǎn)錄酶抑制劑與HIV成熟抑制劑BVM的雙靶點(diǎn)化合物,且在肝微粒體酶作用下易代謝,為后期對(duì)其活性的優(yōu)化奠定了基礎(chǔ)。
[Abstract]:AIDS (acquired immunodeficiency syndrome, AIDS) is by the human immunodeficiency virus (human immunodeficiency, virus, HIV) infection caused by disease, but also the medical profession is difficult to cure the ills of one of the.2016 global AIDS statistics estimated that in 2015 there are 36 million 700 thousand people infected with HIV. Among them, 2 million people are newly infected, 1 million 100 thousand people died of AIDS related the disease. Although there are different stages of life for the virus inhibition of approved drugs 30 kinds, but not completely cure HIV infection therapy. Can effectively relieve patients with highly active antiretroviral therapy in clinical use, reduce the patient's viral load greatly, prolong the life of patients, but the not from HIV therapy and viral clearance in patients on the root, there are obvious side effects, patients with poor compliance, research model Anti HIV drugs provide safety for clinical drug selection, the economy has become particularly important. Our previous study found that non nucleoside reverse transcriptase inhibitors of two kinds of new structure type (non-nucleoside reverse transcriptase inhibitors, NNRTIs) compounds: two aryl amine pyridine (diarylpyridinamines, DAPAs) and two aryl aniline (diarylanilines, DAANs) the compound, HIV wild type and multi drug resistant virus had strong inhibitory activity, and a similar listed drug Riplivirine activity,.Bevirimat replication and can effectively inhibit the newborn of drug-resistant virus (BVM, 3-O- (3 ', 3' -dimethylsuccinyl) betulinic acid) is the first mature inhibitor to enter clinical trials. It is interference CA-SP1 (capsid-spacer protein 1) to CA (capsid) processing, and lead to the accumulation of CA-SP1 assembly release was not mature HIV virus, this virus is not out Have the infection ability, thereby blocking the spread of the HIV virus. Through phase IIa clinical trials to prove its clinical efficacy and safety. As the research continues, this topic will high activity of two aryl aniline compounds bevirimat with appropriate intermediate connection, synthesis of two target compounds, and study activity and in vitro metabolism on the performance of the high activity. In order to find the body, easy metabolism separation, new double target on different targets can also play a role of synergistic anti 1+12 compounds, the role of HIV and HIV drugs to overcome the resistance problem. This paper explores the intermediate and intermediate coupling method, the different types of even in the DAAN nucleus of B ring 2- or 4-, a total synthesis of 20 two aryl aniline derivatives, and two aryl aniline derivatives newly synthesized by anti HIV virus activity and metabolic stability evaluation, including live Of the 16 compounds, the activity and structure-activity relationship of drug like evaluation was as follows: 1) the connection side chain in the DAAN B ring 4-, R2 connection or longer substituent group polarity increases, will reduce the activity; introduction of short chain molecules can maintain or improve the anti HIV activity, short chain performance better than the long chain.2 in the sub resistance) in human liver microsomes model metabolic stability test, compounds B ring 2- two aryl amide substituted aniline compounds than in the B ring 4- amide substituted more unstable, and the B ring 4- ester bond modification than amide bond the side chain is more unstable.3) in the DAAN class B ring 2- amino fatty chain connected to R1, DAAN will decrease the parent nucleus of anti HIV activity, free amino group, the best anti HIV activity, and it also before the conclusion of the study, the amino acid residues in this site and K101 could produce. Anti HIV virus activity The key to explore the synthesis of the 3 groups. The DAAN and BVM double target conjugates, and no detectable anti HIV activity, try to intermediate still needs to be improved. The experiment result shows the metabolic stability in human liver microsomes, double target compounds metabolism half-life of t1/2 were obviously lower than the reference control salt Um F Naylor and TMC278, show that the double the target compounds can occur in metabolic enzymes. DAAN corresponding intermediates were also investigated metabolic stability, metabolic half-life of t1/2 was 10.7 min, 75.3 min, 117.5 min., suggesting a connection side chain in the DAAN class B- 2- amino ring length is longer, the easier it is to further explore metabolism. Guidance for intermediates. In summary, this topic through the study on the synthesis of double targeting non nucleoside reverse transcriptase inhibitor and HIV inhibitor BVM mature compounds, and in liver microsomal enzymes under the action of the latter is easy to metabolism. The optimization of activity lays the foundation.

【學(xué)位授予單位】：中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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本文編號(hào)：1420261