Abstract
Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 μg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6h and bioavailability of 23%.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM Proteins / metabolism*
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ADAMTS4 Protein
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Animals
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacokinetics
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Biphenyl Compounds / pharmacology*
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Drug Design
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Humans
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Male
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Matrix Metalloproteinase 13 / metabolism
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Models, Molecular
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Osteoarthritis / drug therapy
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Procollagen N-Endopeptidase / antagonists & inhibitors*
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Procollagen N-Endopeptidase / metabolism*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Proteoglycans / metabolism
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
Substances
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Biphenyl Compounds
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Protease Inhibitors
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Proteoglycans
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Sulfonamides
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ADAM Proteins
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Matrix Metalloproteinase 13
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Procollagen N-Endopeptidase
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ADAMTS4 Protein