Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
Eur J Med Chem. 2013 Nov;69:399-412. doi: 10.1016/j.ejmech.2013.09.017. Epub 2013 Sep 19.
Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin and leptin signal-transduction pathways. PTP1B inhibitors have emerged as attractive and potent pharmaceutical agents for the treatment of type 2 diabetes and obesity. We identified a series of 2-ethyl-5-phenylthiazole-4-carboxamide (PTA) derivatives, inspired from the ACT scaffold of Scleritodermin A, as a novel class of PTP1B inhibitors. Structure-activity relationship (SAR) analysis and docking studies revealed the molecular basis of PTP1B inhibition by these compounds. PTA derivative 18g was capable of inhibiting intracellular PTP1B and subsequently activating the insulin signaling pathway. Treatment of cells with 18g markedly increased the phosphorylation levels of IRβ and Akt as well as the rate of glucose uptake.
蛋白酪氨酸磷酸酶 1B（PTP1B）被认为是胰岛素和瘦素信号转导途径的关键负调控因子。PTP1B 抑制剂作为治疗 2 型糖尿病和肥胖症的有吸引力和有效的药物已逐渐显现。我们受 Scleritodermin A 的 ACT 支架启发，设计了一系列 2-乙基-5-苯基噻唑-4-甲酰胺（PTA）衍生物，将其作为新型 PTP1B 抑制剂。构效关系（SAR）分析和对接研究揭示了这些化合物抑制 PTP1B 的分子基础。PTA 衍生物 18g 能够抑制细胞内 PTP1B，进而激活胰岛素信号通路。用 18g 处理细胞可显著增加 IRβ 和 Akt 的磷酸化水平以及葡萄糖摄取率。
