RESUMEN
Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 µM, HIV RT RNase H; 13 µM, HIV RT-polymerase; 24 µM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 µM) with a modest window with respect to cytotoxicity (CC(50)=3.3 µM).
Asunto(s)
Fármacos Anti-VIH/farmacología , Inhibidores Enzimáticos/farmacología , VIH-1/enzimología , Ribonucleasa H/antagonistas & inhibidores , Fármacos Anti-VIH/química , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Naftiridinas/química , Naftiridinas/farmacologíaRESUMEN
We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cellular IL2 release.
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Concentración 50 Inhibidora , Interleucina-2/antagonistas & inhibidores , Interleucina-2/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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
We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.