Novel non-carboxylate benzoylsulfonamide-based protein tyrosine phosphatase 1B inhibitors with non-competitive actions

Abstract

A novel series of benzoylsulfonamide derivatives were synthesized and biologically evaluated. Among them, 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzamide (compound 18K) was identified as a protein tyrosine phosphatase 1B (PTP1B) inhibitor with potent and selective inhibitory activity against PTP1B (IC50 = 0.25 μM). Compound 18K functioned as a non-competitive inhibitor and bound to the allosteric site of PTP1B. It also showed high oral absorption in mice (the maximum drug concentration (Cmax) = 45.5 μM at 30 mg/kg), rats (Cmax = 53.6 μM at 30 mg/kg), and beagles (Cmax = 37.8 μM at 10 mg/kg), and significantly reduced plasma glucose levels at 30 mg/kg/d (per os (p.o.)) for one week with no side effects in db/db mice. In conclusion, the substituted benzoylsulfonamide was shown to be a novel scaffold of a noncompetitive and allosteric PTP1B inhibitor, and compound 18K has potential as an efficacious and safe antidiabetic drug as well as a useful tool for investigations of the physiological and pathophysiological effects of allosteric PTP1B inhibition.