Suja Shrestha

Inhibition of IKK-β: a new development in the mechanism of the anti-obesity effects of PTP1B inhibitors SA18 and SA32.

In a previous study, protein tyrosine phosphatase 1B (PTP1B) inhibitors, SA18 and SA32, exhibited anti-obesity effects in a mouse model by suppressing weight gain and improving blood parameters, including free fatty acid (FFA) levels. In a separate study, depletion of the PTP1B gene in mice suppressed weight gain without significant change in FFA levels. The discrepancy in FFA concentrations between the two studies suggested that the in vivo target of the SA compounds might not be limited to PTP1B. In this study, SA18 and SA32 were found to be potent inhibitors of IkappaB Kinase-beta (IKK-beta). In vivo relevance of the inhibitory activity was evaluated in differentiated adipocytes. Inhibition of IKK-beta, in addition to inhibition of PTP1B, in mice treated with the SA compounds, could be a possible mechanism of the compounds biological response including the resistance to diet-induced weight gain and improvement in blood parameters. As potent and cell-permeable IKK-beta inhibitors, SA18 and SA32 could also be valuable in biological experiments.

Derivatives of 1,4-bis(3-hydroxycarbonyl-4-hydroxyl)styrylbenzene as PTP1B inhibitors with hypoglycemic activity

Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC(50) value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.