title: Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.
abstract: Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.
authors.affiliation: Rottapharm Madaus, Medicinal Chemistry Department, via Valosa di Sopra 9, 20900 Monza, Italy. stasi@rottapharm.com
authors.forename: Luigi Piero
authors.initials: LP
authors.lastname: Stasi
authors.forename: Roberto
authors.initials: R
authors.lastname: Artusi
authors.forename: Clara
authors.initials: C
authors.lastname: Bovino
authors.forename: Benedetta
authors.initials: B
authors.lastname: Buzzi
authors.forename: Luca
authors.initials: L
authors.lastname: Canciani
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Colace
authors.forename: Paolo
authors.initials: P
authors.lastname: Garofalo
authors.forename: Silvia
authors.initials: S
authors.lastname: Giambuzzi
authors.forename: Patrice
authors.initials: P
authors.lastname: Larger
authors.forename: Ornella
authors.initials: O
authors.lastname: Letari
authors.forename: Stefano
authors.initials: S
authors.lastname: Mandelli
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Perugini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pucci
authors.forename: Matteo
authors.initials: M
authors.lastname: Salvi
authors.forename: PierLuigi
authors.initials: P
authors.lastname: Toro
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D064446:Orexin Receptors; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D006536:Heptanes; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013141:Spiro Compounds; D003577:Cytochrome P-450 Enzyme System