Synthesis of Novel Protein Tyrosine Phosphatases 1b inhibitors 2, 5-disubstituted oxadiazole

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine-phosphorylated proteins and are negative regulators of tyrosine kinase receptor mediated signaling. PTP1B directly interacts with both the IR and IGF1R. The importance of PTP1B inhepatic metabolism has been demonstrated in vivo and incellular models. Mice lacking the ptpn1 gene exhibit increased insulin sensitivity owing to enhanced phosphorylation of IR in liver and skeletal muscle, resistance to weight gain on a high-fat diet, and an increased basal metabolic rate. So it is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists. Here we investigate a series of 2, 5-disubstituted oxadiazole as novel PTP1B inhibitor. We synthesized few compounds from 2, 5-disubstituted oxadiazole series and screened for the PTP1B inhibition. Compound 9 exhibited significant inhibitory activity against PTP1B. Compound 9 showed IC₅₀ value of 0.46 μmol/L and favorable pharmacodynamics properties in mouse. Structure–activity relationships were explained with the help of molecular modeling approach.