發(fā)布時(shí)間：2018-11-11 10:42

【摘要】：為拓展含串聯(lián)二芳酰胺結(jié)構(gòu)的蛋白酪氨酸磷酸酶1B(PTP1B)抑制劑的化學(xué)空間,將其中的聯(lián)苯二胺結(jié)構(gòu)單元簡(jiǎn)化為芳基酰胺結(jié)構(gòu)單元,設(shè)計(jì)并合成了18個(gè)芳酰胺類化合物.活性測(cè)試結(jié)果表明,部分芳酰胺衍生物對(duì)PTP1B和含SH2結(jié)構(gòu)域蛋白酪氨酸磷酸酶2(SHP2)顯示了一定強(qiáng)度的抑制活性.其中化合物3c[IC_(50)=(5.13±0.21)μmol/L]對(duì)PTP1B顯示了中等強(qiáng)度的抑制活性,并且對(duì)其他亞型[T細(xì)胞蛋白酪氨酸磷酸酶(TCPTP)、含SH2結(jié)構(gòu)域蛋白酪氨酸磷酸酶1(SHP1)和SHP2]顯示了一定的選擇性.有意思的是,化合物12對(duì)SHP2顯示了中等強(qiáng)度的抑制活性[IC50=(7.47±1.26)μmol/L],對(duì)PTP1B、TCPTP以及SHP1顯示了2倍的選擇性,為發(fā)現(xiàn)新型選擇性SHP2抑制劑提供了新的骨架類型.
[Abstract]:In order to expand the chemical space of protein tyrosine phosphatase 1B (PTP1B) inhibitor containing diarylamides in series, the biphenyl diamine structure unit was simplified to aryl amide structure unit, and 18 aromatic amides were designed and synthesized. The results of activity test showed that some aromatic amide derivatives showed strong inhibitory activity against PTP1B and SH2 domain protein tyrosine phosphatase 2 (SHP2). Among them, compound 3c [IC_ (50) = (5.13 鹵0.21) 渭 mol/L] showed moderate inhibitory activity to PTP1B, and showed moderate inhibitory activity to other subtypes [T cell protein tyrosine phosphatase (TCPTP),]. Tyrosine phosphatase 1 (SHP1) and SHP2 containing SH2 domain proteins showed certain selectivity. Interestingly, compound 12 showed moderate inhibitory activity to SHP2 [(7.47 鹵1.26) 渭 mol/L], double selectivity to PTP1B,TCPTP and SHP1, which provided a new skeleton type for the discovery of novel selective SHP2 inhibitors.
【作者單位】： 江南大學(xué)藥學(xué)院;中國(guó)科學(xué)院上海藥物研究所國(guó)家新藥篩選中心新藥研究國(guó)家重點(diǎn)實(shí)驗(yàn)室;
【基金】：國(guó)家自然科學(xué)基金(No.21472069) 中國(guó)科學(xué)院上海藥物研究所新藥研究國(guó)家重點(diǎn)實(shí)驗(yàn)室(No.SIMM1302KF-05)資助項(xiàng)目~~
【分類號(hào)】：O625.525
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本文編號(hào)：2324598