RESUMEN
Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
Asunto(s)
Benzofuranos/química , Inhibidores Enzimáticos/química , Epóxido Hidrolasas/antagonistas & inhibidores , Animales , Benzofuranos/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.
