The Design and Evaluation of Mono-charged Inhibitors of PTP1B

Protein Tyrosine Phosphatase 1B (PTP1B) has been demonstrated to negatively regulate insulin receptor activity and has thus been identified as a therapeutic target for treatment of type 2 diabetes. The identification of cell-permeable PTP1B inhibitors has been challenging, as active site inhibitors must mimic a dianionic phosphotyrosine. We have developed monocharged, small molecule inhibitors to address the issue of permeability while maintaining potency against PTP1B. After identifying an aniline acid series of inhibitors, a more drug-like series of heterocyclic acids was designed and prepared. The design, synthesis, and in vitro activities of these monocharged inhibitors are presented.