RESUMO
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%.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Compostos de Bifenilo/farmacologia , Pró-Colágeno N-Endopeptidase/antagonistas & inibidores , Pró-Colágeno N-Endopeptidase/metabolismo , Inibidores de Proteases/farmacologia , Sulfonamidas/farmacologia , Proteína ADAMTS4 , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Desenho de Fármacos , Humanos , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Modelos Moleculares , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Proteoglicanas/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
The prevention of aggrecan (a key component of cartilage) cleavage via the inhibition of aggrecanase-1 may provide a unique opportunity to stop the progression of cartilage degradation in osteoarthritis. The evaluation of a series of biphenylsulfonamides resulted in the identification of the ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides analogs (19-21 and 24) with improved Agg-1 inhibition and MMP-2, MMP-13 activity.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Química Farmacêutica/métodos , Osteoartrite/tratamento farmacológico , Pró-Colágeno N-Endopeptidase/antagonistas & inibidores , Pró-Colágeno N-Endopeptidase/metabolismo , Sulfonamidas/síntese química , Proteína ADAMTS4 , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Modelos Químicos , Conformação Molecular , Proteoglicanas/química , Sulfonamidas/farmacologiaRESUMO
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%.
