title: Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.
abstract: Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
authors.affiliation: Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ahmed
authors.forename: Michael A
authors.initials: MA
authors.lastname: Briggs
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: Tania
authors.initials: T
authors.lastname: Buck
authors.forename: Lorraine
authors.initials: L
authors.lastname: Campbell
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Deeks
authors.forename: Ashley
authors.initials: A
authors.lastname: Garner
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.forename: Dieter W
authors.initials: DW
authors.lastname: Hamprecht
authors.forename: Vicky
authors.initials: V
authors.lastname: Holland
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Moss
authors.forename: Jenifer
authors.initials: J
authors.lastname: Powles
authors.forename: Jon T
authors.initials: JT
authors.lastname: Seal
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: Mervyn
authors.initials: M
authors.lastname: Thompson
authors.forename: Brenda
authors.initials: B
authors.lastname: Trail
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Kim
authors.initials: K
authors.lastname: Winborn
authors.forename: David R
authors.initials: DR
authors.lastname: Witty
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D008968:Molecular Conformation; D010539:Permeability; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor