ABSTRACT
A new series of hydroxamic acid-based matrix metalloproteinase (MMP) inhibitors containing a unique phosphinamide motif derived from D-amino acid was designed, synthesized, and tested for enzyme inhibition. Compounds with an R configuration at phosphorus were found to be potent MMP inhibitors while molecules with the S configuration were almost inactive. Structure-activity relationship studies of the series led to the discovery of the potent inhibitor 16 with IC50 = 20.5 nM and 24.4 nM against fibroblast collagenase (MMP-1) and stromelysin (MMP-3), respectively. The binding mode of this novel phosphinamide-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 16.
Subject(s)
Hydroxamic Acids/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Organophosphorus Compounds/chemical synthesis , Protease Inhibitors/chemical synthesis , Binding Sites , Crystallography, X-Ray , Drug Design , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/metabolism , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 1 , Matrix Metalloproteinase 13 , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 7 , Matrix Metalloproteinase 9 , Matrix Metalloproteinase Inhibitors , Models, Molecular , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/metabolism , Organophosphorus Compounds/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Recombinant Proteins/antagonists & inhibitors , Stereoisomerism , Structure-Activity RelationshipSubject(s)
Metalloendopeptidases/antagonists & inhibitors , Piperazines/chemical synthesis , Crystallography, X-Ray , Matrix Metalloproteinase 1 , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 7 , Matrix Metalloproteinase 9 , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/metabolism , Models, Molecular , Molecular Conformation , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) with selectivity for the COX-2 isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone side chains from active DHDMBFs were used to investigate the effects of changes in the DHDMBF "core": the size and identity of the heterocycle and the substituent requirements of the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes can be accommodated, but no structure was clearly superior to the DHDMBF structure.
