Design, synthesis, and biological evaluation of novel 2-ethyl-5-phenylthiazole-4-carboxamide derivatives as protein tyrosine phosphatase 1B inhibitors with improved cellular efficacy

• A series of 2-ethyl-5-phenylthiazole-4-carboxamide derivatives were synthesized.
• Phenyl substitution at C5 position of thiazole ring improved cellular efficacy.
• Compound 18g displayed a submicromolar IC50 value against PTP1B.
• Compound 18g activated insulin signaling pathway by inhibiting intracellular PTP1B.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin and leptin signal-transduction pathways. PTP1B inhibitors have emerged as attractive and potent pharmaceutical agents for the treatment of type 2 diabetes and obesity. We identified a series of 2-ethyl-5-phenylthiazole-4-carboxamide (PTA) derivatives, inspired from the ACT scaffold of Scleritodermin A, as a novel class of PTP1B inhibitors. Structure–activity relationship (SAR) analysis and docking studies revealed the molecular basis of PTP1B inhibition by these compounds. PTA derivative 18g was capable of inhibiting intracellular PTP1B and subsequently activating the insulin signaling pathway. Treatment of cells with 18g markedly increased the phosphorylation levels of IRβ and Akt as well as the rate of glucose uptake.

A series of 2-ethyl-5-phenylthiazole-4-carboxamide (PTA) derivatives were synthesized and identified as a novel class of PTP1B inhibitors. Among them, 18g displayed lowest IC50 value and good cellular efficacy.Figure optionsDownload as PowerPoint slide