title: Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists.
abstract: A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline SpA, Medicines Research Centre, Verona, Italy. colin.p.leslie@gsk.com
authors.forename: Colin P
authors.initials: CP
authors.lastname: Leslie
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bentley
authors.forename: Matteo
authors.initials: M
authors.lastname: Biagetti
authors.forename: Stefania
authors.initials: S
authors.lastname: Contini
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Thorsten
authors.initials: T
authors.lastname: Genski
authors.forename: Sebastien
authors.initials: S
authors.lastname: Guery
authors.forename: Angelica
authors.initials: A
authors.lastname: Mazzali
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Merlo
authors.forename: Domenica A
authors.initials: DA
authors.lastname: Pizzi
authors.forename: Fabiola
authors.initials: F
authors.lastname: Sacco
authors.forename: Catia
authors.initials: C
authors.lastname: Seri
authors.forename: Michela
authors.initials: M
authors.lastname: Tessari
authors.forename: Laura
authors.initials: L
authors.lastname: Zonzini
authors.forename: Laura
authors.initials: L
authors.lastname: Caberlotto
mesh_terms: D000818:Animals; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; D003577:Cytochrome P-450 Enzyme System