RESUMEN
Substituted azaquinazolinones were identified as antagonists of the GHSr-1A receptor for the treatment of type II diabetes and obesity. Optimisation for potency and LogD lead to the identification of orally bioavailable, potent antagonists with improved selectivity over hERG.
Asunto(s)
Compuestos Aza/síntesis química , Hipoglucemiantes/síntesis química , Quinazolinonas/síntesis química , Receptores de Ghrelina/antagonistas & inhibidores , Administración Oral , Animales , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Disponibilidad Biológica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Cinética , Masculino , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Quinazolinonas/farmacocinética , Quinazolinonas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadRESUMEN
OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.
Asunto(s)
Leucemia de Mastocitos/terapia , Proteínas Proto-Oncogénicas c-kit/fisiología , Quinolinas/farmacología , Tiofenos/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Femenino , Humanos , Leucemia de Mastocitos/patología , Ratones , Ratones Desnudos , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Tiofenos/administración & dosificación , Tiofenos/farmacocinética , Trasplante Heterólogo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr â¼13-16:1) were obtained using lithium enolates of phenyl esters in combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (-)-epilupinine ((-)-2) and (-)-tashiromine ((-)-1) in two further steps.