RESUMEN
A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Humanos , Quinasa I-kappa B , Cinética , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).
Asunto(s)
Antiinflamatorios/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Animales , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Edema/prevención & control , Humanos , Quinasa I-kappa B , Cinética , Ratones , Modelos Moleculares , Estructura Molecular , Piridinas/síntesis química , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha).
