title: Discovery of Lu AA33810: a highly selective and potent NPY5 antagonist with in vivo efficacy in a model of mood disorder.
abstract: The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.
authors.affiliation: Department of Chemical & Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Packiarajan
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Marzabadi
authors.forename: Mahesh
authors.initials: M
authors.lastname: Desai
authors.forename: Yalei
authors.initials: Y
authors.lastname: Lu
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Noble
authors.forename: Wai C
authors.initials: WC
authors.lastname: Wong
authors.forename: Vrej
authors.initials: V
authors.lastname: Jubian
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Toni D
authors.initials: TD
authors.lastname: Wolinsky
authors.forename: Hualing
authors.initials: H
authors.lastname: Zhong
authors.forename: Mary W
authors.initials: MW
authors.lastname: Walker
authors.forename: Ove
authors.initials: O
authors.lastname: Wiborg
authors.forename: Kim
authors.initials: K
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001582:Benzothiepins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D051379:Mice; D015394:Molecular Structure; D019964:Mood Disorders / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001582:Benzothiepins; C539254:N-((4-((4,5-dihydro(1)benzothiepino(5,4-d)thiazol-2-yl)amino)cyclohexyl)methyl)methanesulfonamide; D017476:Receptors, Neuropeptide Y; D013449:Sulfonamides; C100568:neuropeptide Y5 receptor