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Structure-Based Optimization of Protein Tyrosine Phosphatase 1B Inhibitors: From the Active Site to the Second Phosphotyrosine Binding Site

2007; American Chemical Society; Volume: 50; Issue: 19 Linguagem: Inglês

10.1021/jm0702478

1520-4804

Douglas Wilson, Zhao‐Kui Wan, Weixin Xu, Steven J. Kirincich, Bruce Follows, Diane Joseph‐McCarthy, Kenneth W. Foreman, Alessandro Moretto, Junjun Wu, Min Zhu, Eva Binnun, Yanling Zhang, May Tam, David V. Erbe, James F. Tobin, Xin Xu, Louis Leung, Adam D. Shilling, S. Y. K. TAM, Tarek S. Mansour, Jinbo Lee,

Bioactive Compounds and Antitumor Agents

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guided by X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient 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 membrane permeability of PTP1B inhibitors.