RESUMO
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).
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores Enzimáticos/farmacologia , HIV-1/enzimologia , Ribonuclease H/antagonistas & inibidores , Fármacos Anti-HIV/química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Naftiridinas/química , Naftiridinas/farmacologiaRESUMO
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.
Assuntos
Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Concentração Inibidora 50 , Interleucina-2/antagonistas & inibidores , Interleucina-2/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , Naftiridinas/química , Piperidinas/química , Quinolonas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Artrite Experimental , Colágeno/química , Dexametasona/química , Cães , Haplorrinos , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/metabolismo , Camundongos , Modelos Químicos , Ratos , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
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.