ABSTRACT
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.
Subject(s)
Indazoles/pharmacology , Obesity/drug therapy , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Cardiovascular Diseases/chemically induced , Ether-A-Go-Go Potassium Channels/drug effects , Humans , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Mice , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Obesity Agents/chemistry , Carbolines/chemistry , Obesity/drug therapy , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Carbolines/pharmacology , Carbolines/therapeutic use , Mice , Structure-Activity RelationshipABSTRACT
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).
