RESUMEN
A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.
Asunto(s)
Benzopiranos/química , Inhibidores Enzimáticos/química , Esterasas/antagonistas & inhibidores , Animales , Benzopiranos/farmacocinética , Benzopiranos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Esterasas/metabolismo , Fémur/fisiología , Semivida , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/fisiopatología , Unión Proteica , Relación Estructura-ActividadRESUMEN
A series of potent piperidine-linked cytosine derivatives were prepared as inhibitors of deoxycytidine kinase (dCK). Compound 9h was discovered to be a potent inhibitor of dCK and shows a good combination of cellular potency and pharmacokinetic parameters. Compound 9h blocks the incorporation of radiolabeled cytosine into mouse T-cells in vitro, as well as in vivo in mice following a T-cell challenge.
Asunto(s)
Desoxicitidina Quinasa/antagonistas & inhibidores , Flucitosina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Diseño de Fármacos , Flucitosina/síntesis química , Flucitosina/química , Humanos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.