ABSTRACT
A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.
Subject(s)
Body Weight/drug effects , Imidazoles/chemical synthesis , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Animals , Binding Sites , Body Weight/physiology , Cells, Cultured , Imidazoles/pharmacology , Rats , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.