丙二酸类PTP1B抑制剂的设计、合成及活性研究

Design,synthesis and evaluation of malonic acid-based PTP1B inhibitors

蛋白酪氨酸磷酸酶(protein tyrosine phosphatase,PTP)1B是治疗2型糖尿病(T2DM)及肥胖症的潜在靶点。磷酸酪氨酸(pTyr)是PTP1B去磷酸化作用的底物,本文以丙二酸基团模拟pTyr分子中的磷酸酯,设计合成了丙二酸类PTP1B抑制剂1～7。抑酶活性评价显示,化合物3和4对人重组PTP1B的半数抑制浓度IC50分别为7.66和1.88μmol.L-1。

Protein tyrosine phosphatase（PTP） 1B is a potential target for the treatment of diabetes and obesity.Phosphotyrosine（pTyr） is the substrate for PTP1B dephosphorylation.Malonic acid moiety was used herein as a mimic of the phosphate group in pTyr,and novel malonic acid derivatives 1-7 were designed,synthesized and evaluated as PTP1B inhibitors.Results from enzymatic assays indicated that compounds 3 and 4 exhibited potent inhibition against human recombinant PTP1B with IC50 values of 7.66 and 1.88 μmol·L-1,respectively.