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1.
Bioorg Med Chem Lett ; 16(15): 3927-31, 2006 Aug 01.
Article in English | MEDLINE | ID: mdl-16723229

ABSTRACT

A series of butynyloxyphenyl beta-sulfone piperidine hydroxamate TACE inhibitors was designed and synthesized. The resulting structure-activity relationship and MMP selectivity of the series were examined. Of the compounds investigated, 17s has excellent in vitro potency against isolated TACE enzyme, shows good selectivity over MMP-1, -2, -7, -8, -9, -13, and -14, and oral activity in an in vivo mouse model of TNF-alpha production.


Subject(s)
ADAM Proteins/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacology , ADAM17 Protein , Animals , Drug Design , Mice , Piperidines/chemistry , Structure-Activity Relationship
3.
Drug Des Discov ; 18(4): 123-6, 2003.
Article in English | MEDLINE | ID: mdl-15553924

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.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hydroxamic Acids/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , ADAM Proteins , ADAM17 Protein , Cells, Cultured , Humans , Hydroxamic Acids/pharmacology , Indicators and Reagents , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Matrix Metalloproteinase 13 , Matrix Metalloproteinase Inhibitors , Monocytes/drug effects , Monocytes/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Binding , Structure-Activity Relationship , Substrate Specificity , Tumor Necrosis Factor-alpha/biosynthesis
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