Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists

A series of spiroindoline-3,4′-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10 mg/kg.

Graphical abstractA series of potent and orally active spiroindoline-3,4′-piperidine derivatives NPY Y5 receptor antagonists are described.Figure optionsDownload full-size imageDownload as PowerPoint slide