title: Structure-activity relationship studies and sleep-promoting activity of novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 2.
abstract: 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.
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Sifferlen
authors.forename: Ralf
authors.initials: R
authors.lastname: Koberstein
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cottreel
authors.forename: Amandine
authors.initials: A
authors.lastname: Boller
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
authors.forename: John
authors.initials: J
authors.lastname: Gatfield
authors.forename: Catherine
authors.initials: C
authors.lastname: Brisbare-Roch
authors.forename: Francois
authors.initials: F
authors.lastname: Jenck
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D000068796:Orexin Receptor Antagonists; D011719:Pyrazines