Dual inhibitors of
protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell
protein phosphotyrosine phosphatase (
TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both
enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on
body weight and food intake in obese rats. Likewise, the effects of the compounds on
glucose tolerance,
insulin resistance, as well as
insulin and
leptin levels, have been evaluated. In addition, the effects on PTP1B,
TC-PTP, and Src homology region 2 domain-containing phosphatase-1 (SHP1), as well as the
insulin and
leptin receptors gene expressions, have been assessed. In obese male Wistar rats, a five-day administration of all studied compounds led to a decrease in
body weight and food intake, improved
glucose tolerance, attenuated
hyperinsulinemia, hyperleptinemia and
insulin resistance, and also compensatory increased expression of the PTP1B and
TC-PTP genes in the liver. The highest activity was demonstrated by 6-Chloro-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 3) and 6-Bromo-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 4) with mixed PTP1B/
TC-PTP inhibitory activity. Taken together, these data shed light on the pharmacological implications of PTP1B/
TC-PTP dual inhibition, and on the promise of using mixed PTP1B/
TC-PTP inhibitors to correct metabolic disorders.