Structure-Based Optimization of Protein Tyrosine Phosphatase 1B Inhibitors: From the Active Site to the Second Phosphotyrosine Binding Site
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- 作者：Douglas P. Wilson ; Zhao-Kui Wan ; Wei-Xin Xu ; Steven J. Kirincich ; Bruce C. Follows ; Diane Joseph-McCarthy ; Kenneth Foreman ; Alessandro Moretto ; Junjun Wu ; Min Zhu ; Eva Binnun ; Yan-Ling Zhang ; May Tam
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：September 20, 2007
- 年：2007
- 卷：50
- 期：19
- 页码：4681 - 4698
- 全文大小：550K
- 年卷期：v.50,no.19(September 20, 2007)
- ISSN：1520-4804
文摘
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathwaysand thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar leadcompound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from theenzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guidedby X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in anefficient manner. Compounds from this chemical series were found to be actively transported into hepatocytes.This active uptake into target tissues could be one of the possible avenues to overcome the poor membranepermeability of PTP1B inhibitors.