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%.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Biphenyl Compounds/chemistry , Carboxylic Acids , Enzyme Inhibitors , Procollagen N-Endopeptidase/antagonists & inhibitors , Sulfonamides/chemistry , ADAMTS4 Protein , Administration, Oral , Animals , 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 , Proteoglycans/drug effects , Proteoglycans/metabolism , Rats , Structure-Activity RelationshipABSTRACT
New molecular platforms which are hybrids of two scaffolds-namely, beta-d-glucose and benzodiazepine, each able to bind several proteins-were designed, synthesized and functionalized to serve as probes for broad biological screening. Herein, we describe the syntheses and chemical properties of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and (-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction conditions, even at concentrations of only 0.001 N. Consideration of factors affecting the conformation of amide bonds and their effects on cyclization reactions led us to alkylate the amide bond. As expected, the cyclization of the N-methyl derivative (-)-110 afforded exclusively the unimolecular cyclization product (+)-111. These compounds are only now undergoing broad screening and represent therefore at present a "prospecting library."
