RESUMEN
Substrate-like difluoroketones have been prepared as potential inhibitors of MMP-13. Weak inhibition was seen with the key target 2. This and the more potent activity of intermediate 7b illustrates that hydrated ketones can be used to inhibit MMP-13 and perhaps other members of this class of enzymes.
Asunto(s)
Cetonas/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Diseño de Fármacos , Cetonas/química , Cetonas/farmacología , Cinética , Metaloproteinasa 13 de la Matriz , Estructura Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S2 pocket of these enzymes were designed. The synthesis and testing of 2 suggested that binding was occurring as hypothesized. Structure determination of a co-crystal of 2 bound to the catalytic domain of MMP-1 confirmed the binding mode. Substituents binding into S2, S1', S2' and S3', were optimized yielding compounds with low double-digit nM IC50's against these enzymes.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Ácidos Fosfínicos/farmacología , Sitios de Unión , Colagenasas/farmacocinética , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Concentración 50 Inhibidora , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 13 de la Matriz , Modelos MolecularesRESUMEN
The SAR of a series of 2-(7-chromanyl)benzoic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in the benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chromanol substituent were potent LTB4 receptor antagonists, the increased lipophilicity imparted by the additional phenyl substituent led to decreased potency in the presence of plasma proteins. From among the potent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development.