Abstract
Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%.
MeSH terms
-
ADAM Proteins / antagonists & inhibitors*
-
ADAMTS4 Protein
-
Administration, Oral
-
Animals
-
Biphenyl Compounds / chemistry*
-
Carboxylic Acids* / chemical synthesis
-
Carboxylic Acids* / chemistry
-
Carboxylic Acids* / pharmacology
-
Collagenases / metabolism
-
Crystallography, X-Ray
-
Drug Evaluation, Preclinical
-
Enzyme Inhibitors* / chemical synthesis
-
Enzyme Inhibitors* / chemistry
-
Enzyme Inhibitors* / pharmacology
-
Matrix Metalloproteinase 13
-
Matrix Metalloproteinase Inhibitors
-
Models, Molecular
-
Molecular Structure
-
Procollagen N-Endopeptidase / antagonists & inhibitors*
-
Proteoglycans / drug effects
-
Proteoglycans / metabolism
-
Rats
-
Structure-Activity Relationship
-
Sulfonamides / chemistry*
Substances
-
Biphenyl Compounds
-
Carboxylic Acids
-
Enzyme Inhibitors
-
Matrix Metalloproteinase Inhibitors
-
Proteoglycans
-
Sulfonamides
-
ADAM Proteins
-
Collagenases
-
Matrix Metalloproteinase 13
-
Mmp13 protein, rat
-
Procollagen N-Endopeptidase
-
ADAMTS4 Protein