title: New quinoline NK3 receptor antagonists with CNS activity.
abstract: Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
authors.affiliation: Medicinal Chemistry, Neuroscience CEDD GlaxoSmithKline Research & Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Paul.W.Smith@GSK.com
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wyman
authors.forename: Peter
authors.initials: P
authors.lastname: Lovell
authors.forename: Caroline
authors.initials: C
authors.lastname: Goodacre
authors.forename: Halina T
authors.initials: HT
authors.lastname: Serafinowska
authors.forename: Antonio
authors.initials: A
authors.lastname: Vong
authors.forename: Frank
authors.initials: F
authors.lastname: Harrington
authors.forename: Sean
authors.initials: S
authors.lastname: Flynn
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bradley
authors.forename: Rod
authors.initials: R
authors.lastname: Porter
authors.forename: Sara
authors.initials: S
authors.lastname: Coggon
authors.forename: Graham
authors.initials: G
authors.lastname: Murkitt
authors.forename: Kirsten
authors.initials: K
authors.lastname: Searle
authors.forename: David R
authors.initials: DR
authors.lastname: Thomas
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
authors.forename: William
authors.initials: W
authors.lastname: Martin
authors.forename: Zining
authors.initials: Z
authors.lastname: Wu
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
mesh_terms: D000588:Amines / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects*; D002540:Cerebral Cortex / Q000196:embryology; D005849:Gerbillinae; D008297:Male; D008956:Models, Chemical; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*
chemical_list: D000588:Amines; C539893:GSK256471; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C109112:SB 222200; C106716:SB 223412