Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists

The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293—human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC50s. Specific examples exhibit IC50 values of ∼20 nM using human orexin A as the peptide agonist for the orexin-2 receptor.

Graphical abstractThe synthesis and evaluation of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide