title: 4-Substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with superior pharmacological and pharmacokinetic parameters.
abstract: A novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60%. In addition, a straightforward two-step procedure for the assembly of the target molecules is also presented.
authors.affiliation: Discovery Biology, F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Alberati
authors.forename: Dominik
authors.initials: D
authors.lastname: Hainzl
authors.forename: Synèse
authors.initials: S
authors.lastname: Jolidon
authors.forename: Anke
authors.initials: A
authors.lastname: Kurt
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinard
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Zimmerli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008861:Microsomes; D008956:Models, Chemical; D018847:Opioid Peptides / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013696:Temperature; D000097629:Nociceptin
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; D018847:Opioid Peptides; D010880:Piperidines; D020033:Protein Isoforms; D013141:Spiro Compounds; D000097629:Nociceptin; C092509:KCNH6 protein, human; C493271:SLC6A5 protein, human; C493268:SLC6A9 protein, human