RESUMEN
The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).
Asunto(s)
Cartílago/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz , Piperidinas/farmacología , Inhibidores de Proteasas/síntesis química , Sulfonamidas/farmacología , Animales , Cartílago/metabolismo , Bovinos , Colágeno Tipo II/metabolismo , Cristalografía por Rayos X , Concentración 50 Inhibidora , Piperidinas/administración & dosificación , Piperidinas/síntesis química , Piperidinas/farmacocinética , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Proteoglicanos/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
To improve the pharmacokinetics of a previously reported series of dipeptidyl nitrile cathepsin B inhibitors, the P(2)-P(3) amide group was replaced with an arylamine. Further optimization of this template resulted in highly potent and selective inhibitors with excellent oral availability.