Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors

The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 μg/mL and has an oral bioavailability in rat of 35%. Aggrecanases are recently discovered enzymes that cleave aggreca...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2006-01, Vol.16 (2), p.311-316
Hauptverfasser:	Xiang, Jason S., Hu, Yonghan, Rush, Thomas S., Thomason, Jennifer R., Ipek, Manus, Sum, Phaik-Eng, Abrous, Leila, Sabatini, Joshua J., Georgiadis, Katy, Reifenberg, Erica, Majumdar, Manas, Morris, Elisabeth A., Tam, Steve
Format:	Artikel
Sprache:	eng
Schlagworte:	ADAM Proteins - antagonists & inhibitors ADAMTS4 Protein Administration, Oral Aggrecanase-1 inhibitor Animals Benzofuran Biological and medical sciences Biphenyl Compounds - chemistry Biphenylsulfonamide carboxylate Bones, joints and connective tissue. Antiinflammatory agents 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 Medical sciences Models, Molecular Molecular Structure Osteoarthritis Pharmacology. Drug treatments Procollagen N-Endopeptidase - antagonists & inhibitors Proteoglycans - drug effects Proteoglycans - metabolism Rats Structure-Activity Relationship Sulfonamides - chemistry
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Zusammenfassung:	The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 μg/mL and has an oral bioavailability in rat of 35%. 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 μg/mL and has an oral bioavailability in rat of 35%.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2005.10.001