Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors

Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the "bioisosteric principle" were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC₅₀ = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (P_app = 2.41 × 10^-6 cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity.