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.
Subject(s)
Orexin Receptor Antagonists/pharmacology , Orexin Receptors/metabolism , Pyrrolidinones/pharmacology , Sleep/drug effects , Administration, Oral , Animals , Dose-Response Relationship, Drug , Humans , Lactams/administration & dosage , Lactams/pharmacology , Molecular Structure , Orexin Receptor Antagonists/chemical synthesis , Orexin Receptor Antagonists/chemistry , Pyrrolidinones/chemical synthesis , Pyrrolidinones/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.
