RESUMEN
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacocinética , Animales , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirimidinonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Trasplante Heterólogo , Regulación hacia ArribaRESUMEN
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Inhibidores de la Dipeptidil-Peptidasa IV , Glicoproteínas/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Piridinas/síntesis química , Pirrolidinas/síntesis química , Adenosina Desaminasa/química , Administración Oral , Animales , Sitios de Unión , Células CACO-2 , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/química , Perros , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Glicoproteínas/química , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Macaca fascicularis , Modelos Moleculares , Estructura Molecular , Piridinas/farmacocinética , Piridinas/farmacología , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of potent steroidal glucocorticoid receptor antagonists has been discovered. After conjugation to cholic acid, the compounds retained an affinity for GR in vitro and had modest in vivo efficacy.
