Sulfonate Ester Hydroxamic Acids as Potent and Selective Inhibitors of TACE Enzyme

Abstract

Sulfonamide hydroxamate derivatives of anthranilic acids are known to be potent inhibitors of cell-free TACE enzyme. However, compounds of this structural class with both high potency and high selectivity for TACE over matrix metalloproteinases (MMPs) are uncommon. Replacement of the sulfonamide functionality with an isosteric sulfonate ester has resulted in a series of sulfonate ester hydroxamates, 2a-e, with excellent activity against TACE and excellent selectivity over MMP-1 and MMP-13. Although compounds 2a-e possess good permeability in a PAMPA assay, they are only weakly active as inhibitors of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production in human monocytic THP-1 cells. Protein binding affinity also does not predict the lack of cellular activity for these analogs.