RESUMO
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%.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Compostos de Bifenilo/química , Ácidos Carboxílicos , Inibidores Enzimáticos , Pró-Colágeno N-Endopeptidase/antagonistas & inibidores , Sulfonamidas/química , Proteína ADAMTS4 , Administração Oral , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Colagenases/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Metaloproteinase 13 da Matriz , Inibidores de Metaloproteinases de Matriz , Modelos Moleculares , Estrutura Molecular , Proteoglicanas/efeitos dos fármacos , Proteoglicanas/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
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."