Discovery and structural modification of novel inhibitors of PTP1B inspired by the ACT fragment of scleritodermin A

Abstract

A series of compounds synthesized from a key intermediate in the total synthesis of Scleritodermin A containing a novel conjugated thiazole moiety, 2-(1-amino-2-p-hydroxyphenylethane)-4-(4-carboxy-2,4-dimethyl-2Z,4E-propadiene)-thiazole (ACT), were discovered to be potent inhibitors of protein tyrosine phosphatase 1B, with IC₅₀ values in the low micromolar range. Structure–activity relationships around the scaffold were investigated and some compounds exhibited more potent PTP1B inhibitory activity and improved specificities compared with the original hit.