title: Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists.
abstract: A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.
authors.affiliation: Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #2A1, Jupiter, FL 33458, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Xinyi
authors.initials: X
authors.lastname: Song
authors.forename: Purva
authors.initials: P
authors.lastname: Bali
authors.forename: Anthony
authors.initials: A
authors.lastname: Smith
authors.forename: Claudia Ruiz
authors.initials: CR
authors.lastname: Bayona
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Patricia H
authors.initials: PH
authors.lastname: McDonald
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D064446:Orexin Receptors; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D064446:Orexin Receptors; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide