title: Proline bis-amides as potent dual orexin receptor antagonists.
abstract: A series of OX(2)R/OX(1)R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bergman
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.forename: Swati P
authors.initials: SP
authors.lastname: Mercer
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: Duane R
authors.initials: DR
authors.lastname: Reiss
authors.forename: Richard W
authors.initials: RW
authors.lastname: Ransom
authors.forename: C
authors.initials: C
authors.lastname: Meacham Harrell
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Murphy
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D009479:Neuropeptides / Q000737:chemistry / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D011392:Proline