Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor

A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (Ki’s ⩽ 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R Ki value by 25-fold over a 24-h time-period.

Graphical abstractA novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists.Figure optionsDownload full-size imageDownload as PowerPoint slide