苯氧乙酸类PTP1B抑制剂的设计、合成及活性研究

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

摘要: 蛋白酪氨酸磷酸酶(protein tyrosine phosphatase, PTP) 1B是治疗2型糖尿病的潜在靶点。已知的PTP1B抑制剂多数为磷酸酪氨酸(pTyr) 模拟物。本文以苯氧乙酸片段模拟pTyr, 设计合成了苯氧乙酸类化合物2a~2g和3a~3c。其中, 化合物2a~2g对PTP1B具有显著的抑制活性, 化合物2g对PTP1B的IC₅₀值达到0.42 μmol·L^-1。化合物2f可提高胰岛素抵抗(IR) 小鼠的胰岛素敏感性, 并降低其血总胆固醇水平, 与胰岛素增敏剂罗格列酮的作用类似。上述研究结果提示PTP1B抑制剂可能对2型糖尿病及其并发症具有综合治疗作用。

Abstract: Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC₅₀ of 0.42 μmol·L^-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.