Abstract
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Animals
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Arthritis / drug therapy
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Arthritis / pathology
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Biological Availability
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cartilage / drug effects
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Cartilage / pathology
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Cattle
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Disease Models, Animal
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / chemistry*
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Hydroxamic Acids / pharmacology*
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Matrix Metalloproteinase Inhibitors*
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Metalloendopeptidases / antagonists & inhibitors*
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Mice
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Rats
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Structure-Activity Relationship
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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Enzyme Inhibitors
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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Adam17 protein, mouse
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Adam17 protein, rat