Substituted pyrrolidin-2-ones: Centrally acting orexin receptor antagonists promoting sleep. Part 2. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Sifferlen, Thierry; Boller, Amandine; Chardonneau, Audrey; Cottreel, Emmanuelle; Gatfield, John; Treiber, Alexander; Roch, Catherine; Jenck, Francois; Aissaoui, Hamed; Williams, Jodi T.; Brotschi, Christine; Heidmann, Bibia; Siegrist, Romain; Boss, Christoph
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 9(2015)
• Page Start: 1884
• Page End: 1891
• Publication Date: 2015-05-01
• Subjects: Orexin receptors -- Dual orexin receptor antagonists -- Selective orexin-2 receptor antagonists -- Sleep -- CNS drug discovery -- Metabolic stability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.035
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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-one46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.