Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
Bioorg Med Chem. 2010 Mar 1;18(5):1773-82. doi: 10.1016/j.bmc.2010.01.055. Epub 2010 Jan 28.
A series of novel thiophene derivatives was designed, synthesized and their activities as competitive inhibitors of protein tyrosine phosphatase (PTPs) 1B (PTP1B) inhibitors were evaluated. All the compounds showed inhibitory potencies, and 10 of these exhibited moderate inhibitory activities with IC(50) values less than 10 microM. The activity of the most potent compound P28 (IC(50)=2.1 microM) was 15 times higher than that of the hit compound P01. Further, four representative compounds (P19, P22, P28, and P31) demonstrated remarkably high selectivities against other PTPs (e.g., PTPalpha, LAR, CD45, and TCPTP); P19 exhibited greater than sixfold selectivity over highly homologous TCPTP. More importantly, these compounds are permeable to cell membranes. The treatment of CHO-K1 cells with P28 (10 microM) resulted in increased phosphorylation of AKT, which suggested extensive cellular activity of this compound. The novel chemical entities reported in this study could be used for overcoming the poor selectivity and low cellular activity of PTP1B inhibitors and might represent a starting point for development of therapeutic PTP inhibitors.
设计、合成了一系列新型噻吩衍生物，并评价了它们作为蛋白酪氨酸磷酸酶（PTPs）1B（PTP1B）抑制剂的活性。所有化合物均表现出抑制活性，其中 10 个化合物对 PTP1B 的抑制活性中等，IC50 值均小于 10 μM。活性最强的化合物 P28（IC50=2.1 μM）的活性比先导化合物 P01 高 15 倍。此外，四个代表性化合物（P19、P22、P28 和 P31）对其他 PTPs（如 PTPalpha、LAR、CD45 和 TCPTP）表现出很高的选择性；P19 对高度同源的 TCPTP 的选择性大于六倍。更重要的是，这些化合物可穿透细胞膜。用 10 μM 的 P28 处理 CHO-K1 细胞可导致 AKT 磷酸化增加，这表明该化合物具有广泛的细胞活性。本研究报道的新型化学实体可用于克服 PTP1B 抑制剂的选择性差和细胞活性低的问题，可能为开发治疗性 PTP 抑制剂提供一个起点。
