title: Substituted pyrrolidin-2-ones: Centrally acting orexin receptor antagonists promoting sleep. Part 2.
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.
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.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Amandine
authors.initials: A
authors.lastname: Boller
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Chardonneau
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cottreel
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: John
authors.initials: J
authors.lastname: Gatfield
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Roch
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Jenck
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Hamed
authors.initials: H
authors.lastname: Aissaoui
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Jodi T
authors.initials: JT
authors.lastname: Williams
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Brotschi
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Bibia
authors.initials: B
authors.lastname: Heidmann
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Siegrist
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: christoph.boss@actelion.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007769:Lactams / Q000008:administration & dosage / Q000494:pharmacology; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012890:Sleep / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D007769:Lactams; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011760:Pyrrolidinones
keywords: CNS drug discovery; Dual orexin receptor antagonists; Metabolic stability; Orexin receptors; Selective orexin-2 receptor antagonists; Sleep