| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1370872 | Bioorganic & Medicinal Chemistry Letters | 2015 | 8 Pages |
Abstract
Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the γ-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.
Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Thierry Sifferlen, Amandine Boller, Audrey Chardonneau, Emmanuelle Cottreel, John Gatfield, Alexander Treiber, Catherine Roch, Francois Jenck, Hamed Aissaoui, Jodi T. Williams, Christine Brotschi, Bibia Heidmann, Romain Siegrist, Christoph Boss,