RESUMEN

The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.

Asunto(s)

Metaloproteinasa 1 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Ácidos Hidroxámicos/química , Metaloproteinasa 13 de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Inhibidores de Proteasas/farmacología , Piranos/química , Relación Estructura-Actividad , Sulfonamidas/química