RESUMEN
Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.
Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Descubrimiento de Drogas , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Animales , Cristalografía por Rayos X , Ciclopropanos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Ratones Noqueados , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Ciclopropanos/síntesis química , Inhibidores de Proteasas/síntesis química , Sulfonamidas/síntesis química , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Animales , Sitios de Unión , Simulación por Computador , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Diseño de Fármacos , Humanos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.