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为拓展含串联二芳酰胺结构的蛋白酪氨酸磷酸酶1B(PTP1B)抑制剂的化学空间,将其中的联苯二胺结构单元简化为芳基酰胺结构单元,设计并合成了18个芳酰胺类化合物.活性测试结果表明,部分芳酰胺衍生物对PTP1B和含SH2结构域蛋白酪氨酸磷酸酶2(SHP2)显示了一定强度的抑制活性.其中化合物3c[IC_(50)=(5.13±0.21)μmol/L]对PTP1B显示了中等强度的抑制活性,并且对其他亚型[T细胞蛋白酪氨酸磷酸酶(TCPTP)、含SH2结构域蛋白酪氨酸磷酸酶1(SHP1)和SHP2]显示了一定的选择性.有意思的是,化合物12对SHP2显示了中等强度的抑制活性[IC50=(7.47±1.26)μmol/L],对PTP1B、TCPTP以及SHP1显示了2倍的选择性,为发现新型选择性SHP2抑制剂提供了新的骨架类型.
In order to broaden the chemical space of protein tyrosine phosphatase 1B (PTP1B) inhibitor containing tandem diramide structure and to simplify the arylene amide structural unit of the diphenylenediamine structural unit therein, 18 aromatic amides were designed and synthesized The results of the activity test showed that some aromatic amide derivatives showed a certain degree of inhibitory activity against PTP1B and SHP2 containing SH2 domain, in which compound 3c [IC 50 = 5.13 ± 0.21) μmol / L] exhibited potent inhibitory activity against PTP1B and showed no effect on other subtypes [T cell protein tyrosine phosphatase (TCPTP), SH2-containing domain tyrosine phosphatase 1 (SHP1) ] Showed some selectivity. Interestingly, Compound 12 showed moderate inhibitory activity on SHP2 [IC50 = (7.47 ± 1.26) μmol / L], showed 2-fold selectivity for PTP1B, TCPTP and SHP1, Provides a new scaffolding type for the discovery of new and selective SHP2 inhibitors.