Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor

A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.

Graphical abstractThe discovery of the potent and orally active PTP1B inhibitor 3g (IC50 = 120 nM, ED50 = 0.8 mg/kg in oGTT) is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide