Discovery of a novel, potent and orally active series of γ-lactams as selective NK1 antagonists

Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious γ-lactam series of selective NK1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.

Graphical abstractReplacement of nitrogen of the cyclic urea lead 1 with a carbon led to identification of a more potent and orally efficacious γ-lactam series of selective NK1 antagonists. Optimization of the γ-lactam series provided several compounds (e.g., 2e) with high affinity and excellent oral CNS activity.Figure optionsDownload full-size imageDownload as PowerPoint slide