Studies On Design, Synthesis And Structure-activity Relationship Of Protein Tyrosine Phosphatase 1B Inhibitors

Type II diabetes is a progressive disease of metabolic dysregulation characterized by insulin resistance in peripheral tissues (liver, muscle, and adipose) and impaired insulin secretion by the pancreas. Modification of proteins by tyrosine phosphorylation is a major mechanism to control their functions, and plays a key role in transmembrane and intracellular signal transduction. The tyrosine phosphorylation state of cellular proteins is controlled by the reciprocal action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases). PTPases cleave the phosphate from the phosphotyrosine residues. More recent evidences have suggested protein tyrosine phosphatase (PTP1B) as a major negative regulator of the insulin signal transduction pathway. Therefore inhibitor of PTP1B are expected to enhance insulin sensitivity and thus be effective terapeutics of the treatment of insulin resistance, Type II diabetes and obesity.Starting from a hit template obtained from high-throughput screening (HTS), we synthesized a series of small molecule libraries based on rational library design along with bioinformatics and catalytic mechanisms of PTP1B. After in vitro enzymatic assays studies on structure-activity relationship, we identified a series of PTP1B inhibitors with skeleton of oleanic acid. Some of them are the most efficient PTP1Binhibitors reported to date. This is the first identification of small-molecule PTPIB inhibitors with structural units totally different from known PTPIB inhibitors. A few PTPIB inhibitors were tested and showed potent activity, high selectivity. This result provides a handhold for the discovery of new drug.In addition, from these lead structures, we discovered several potent activity inhibitors of PTPIB, which could remarkably reduce the level of tyrosine phosphorylation in cell strains CHO/IR. This finding will facilitate the developing of new therapeutic reagents against Type II diabetes.