RESUMEN
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Asunto(s)
Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Pirazolonas/síntesis química , Pirazolonas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Lipopolisacáridos/farmacología , Modelos Moleculares , Conformación Molecular , Osteoartritis/prevención & control , Pirazolonas/química , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/farmacología , Pirimidinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Acetaldehído , Sitios de Unión , Línea Celular , Humanos , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pirimidinas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Pirazoles/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Humanos , Lipopolisacáridos/farmacología , Pirazoles/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Asunto(s)
Pirazolonas/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Lipopolisacáridos/farmacología , Modelos Moleculares , Pirazolonas/administración & dosificación , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
Asunto(s)
Pirazoles/síntesis química , Pirimidinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Técnicas In Vitro , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fosfotransferasas/antagonistas & inhibidores , Fosfotransferasas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
[reaction: see text] Iridium-catalyzed reductive coupling of acrylates and imines provides trans beta-lactams with high diastereoselection. The optimal catalyst allows for the synthesis of trans beta-lactams bearing aromatic, alkenyl, and alkynyl side chains. This reaction appears to proceed through a reductive Mannich addition-cyclization mechanism. Examination of substituent effects reveals a linear Hammett correlation for both the N-aryl group on the imine and the aryloxy group on the acrylate, thereby pointing to rate-determining cyclization in the reaction mechanism.