Ethylenedisalicylic Acid Derivatives as Dual Inhibitors of PTP1B and IKK beta and their Antiobesity and Antidiabetic Effects in Mice

摘要

Ethylenedisalicylic acid (EDSA) was developed as a novel scaffold for dual inhibitors of protein tyrosine phosphatase (PTP) 1B and IkB kinase beta (IKK beta). EDSA is a modified version of methylenedisalicylic acid (MDSA) and contains two salicylate moieties connected by an ethylene moiety. In this study, derivatives of EDSA were synthesized and their inhibitory potencies against PTP1B and IKK beta were investigated. Many of these derivatives exhibited half-maximal inhibitory concentrations (IC(50)s) in the low micromolar range. The metabolic effects of ESA4, 7, and 8 were further examined in a mouse model system. ESA4 and ESA8 significantly suppressed diet-induced weight gain, whereas ESA7 had a marginal effect. ESA4, 7, and 8 also lowered fasting glucose levels and accelerated glucose clearance rates after glucose injection. These observations indicate that EDSA scaffold-based compounds are promising candidates for the treatment of obesity and diabetes.