Novel thiophene derivatives as PTP1B inhibitors with selectivity and cellular activity

Deju Ye, Yu Zhang, Fei Wang, Mingfang Zheng, Xu Zhang, Xiaomin Luo, Xu Shen, Hualiang Jiang, Hong Liu

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 IC50
values less than 10 lM. The activity of the most potent compound P28 (IC50 = 2.1 lM) 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., PTPa, 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 lM)
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.