RESUMEN
A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.
Asunto(s)
Indazoles/farmacología , Obesidad/tratamiento farmacológico , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Enfermedades Cardiovasculares/inducido químicamente , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Indazoles/farmacocinética , Indazoles/uso terapéutico , Ratones , Relación Estructura-ActividadRESUMEN
A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents.
Asunto(s)
Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Piridinas/química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/farmacología , Ratones , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile.
Asunto(s)
Fármacos Antiobesidad/química , Carbolinas/química , Obesidad/tratamiento farmacológico , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/farmacología , Peso Corporal/efectos de los fármacos , Carbolinas/farmacología , Carbolinas/uso terapéutico , Ratones , Relación Estructura-ActividadRESUMEN
This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.