RESUMO
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.
Assuntos
Indazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Indazóis/farmacocinética , Indazóis/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fármacos Antiobesidade/química , Carbolinas/química , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
An efficient, stereospecific synthesis of the alkaloids senepodine G (2) and cermizine C (1) has been completed using the BF3.Et2O-promoted stereospecific addition of Me2CuLi to alpha,beta-unsaturated lactam 6 to provide lactam 3, the addition of MeMgBr followed by HCl to convert 3 to senepodine G (2) (six steps, 40% overall yield), and the stereospecific NaBH4 reduction of 2 to give cermizine C (1) (seven steps, 40% overall yield).
