RESUMEN
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%.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Compuestos de Bifenilo/farmacología , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Procolágeno N-Endopeptidasa/metabolismo , Inhibidores de Proteasas/farmacología , Sulfonamidas/farmacología , Proteína ADAMTS4 , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Diseño de Fármacos , Humanos , Masculino , Metaloproteinasa 13 de la Matriz/metabolismo , Modelos Moleculares , Osteoartritis/tratamiento farmacológico , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Proteoglicanos/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
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.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Química Farmacéutica/métodos , Osteoartritis/tratamiento farmacológico , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Procolágeno N-Endopeptidasa/metabolismo , Sulfonamidas/síntesis química , Proteína ADAMTS4 , Cartílago/efectos de los fármacos , Cartílago/metabolismo , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Modelos Químicos , Conformación Molecular , Proteoglicanos/química , Sulfonamidas/farmacologíaRESUMEN
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%.
