Discovery of novel orally active ureido NPY Y5 receptor antagonists

We have derived a novel series of neuropeptide Y (NPY) Y5 receptor antagonists from the biphenylurea 3. Cyclohexylurea 21c, a member of the series, is a potent NPY Y5 receptor antagonist that exhibits excellent pharmacokinetic parameters in rats and dogs. On chronic oral administration to diet-induced obese rats, 21c displayed an anti-obesity profile, causing a modest reduction in food intake, a significant decrease in body weight gain, a decrease in adipose mass, and an increase in lean tissue mass.

Graphical abstractStructure–activity relationship studies leading to the potent, selective NPY Y5 receptor antagonist 21c are described. Compound 21c demonstrated dose-dependent anti-obesity effects in diet-induced obese rats after chronic oral administration.Figure optionsDownload full-size imageDownload as PowerPoint slide