Sulfonate ester hydroxamic acids as potent and selective inhibitors of TACE enzyme.
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.
Levin
Jeremy I
JI
Wyeth Research, Pearl River, NY 10965, USA.
Du
Mila T
MT
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human