RESUMEN
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Naftiridinas/química , Piperidinas/química , Quinolonas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Artritis Experimental , Colágeno/química , Dexametasona/química , Perros , Haplorrinos , Humanos , Concentración 50 Inhibidora , Lipopolisacáridos/metabolismo , Ratones , Modelos Químicos , Ratas , Factores de Tiempo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone 4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure-activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog 43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Activación del Canal Iónico/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Triterpenos/farmacología , Bioensayo , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Canal de Potasio Kv1.3 , Modelos Moleculares , Bloqueadores de los Canales de Potasio/química , Relación Estructura-Actividad , Linfocitos T , Triterpenos/químicaRESUMEN
The voltage-gated potassium channel, Kv1.3, is present in human T-lymphocytes. Blockade of Kv1.3 results in T-cell depolarization, inhibition of T-cell activation, and attenuation of immune responses in vivo. A class of benzamide Kv1.3 channel inhibitors has been identified. The structure-activity relationship within this class of compounds in two functional assays, Rb_Kv and T-cell proliferation, is presented. In in vitro assays, trans isomers display moderate selectivity for binding to Kv1.3 over other Kv1.x channels present in human brain.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/efectos de los fármacos , Química Encefálica/efectos de los fármacos , División Celular/efectos de los fármacos , Humanos , Técnicas In Vitro , Canal de Potasio Kv1.3 , Radioisótopos de Rubidio , Estereoisomerismo , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
[reaction: see text] Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis. An unusual fragmentation reaction of ketone 2 with LiCl was discovered. This reaction is general among several similar substrates examined and appears to be specific for the correolide-type E-ring structure (ketone). A mechanism involving a retroaldol reaction, a nucleophilic opening of the epoxide, and a subsequent acetoxy elimination reaction was proposed.
