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.
Subject(s)
Drug Discovery , Lactams/pharmacology , Orexin Receptor Antagonists , Animals , Dose-Response Relationship, Drug , Humans , Lactams/chemistry , Lactams/metabolism , Molecular Structure , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Replacement of the dimethoxyphenyl moiety in the core skeleton of almorexant by appropriately substituted imidazoles afforded novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as potent dual orexin receptor antagonists. We describe in this Letter our efforts to further optimize the potency and brain penetration of these derivatives by fine-tuning of the pivotal phenethyl motif, and we comment on the sleep-promoting activity of selected compounds in a rat electroencephalographic (EEG) model.
Subject(s)
Imidazoles/pharmacology , Orexin Receptor Antagonists , Pyrazines/pharmacology , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.
