title: Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists.
abstract: Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Giancarlo.Z.Trani@gsk.com
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Trani
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Baddeley
authors.forename: Michael A
authors.initials: MA
authors.lastname: Briggs
authors.forename: Tsu T
authors.initials: TT
authors.lastname: Chuang
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Deeks
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Abir A
authors.initials: AA
authors.lastname: Khazragi
authors.forename: Tania L
authors.initials: TL
authors.lastname: Mead
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: Peter H
authors.initials: PH
authors.lastname: Milner
authors.forename: Leann P
authors.initials: LP
authors.lastname: Quinn
authors.forename: Alison M
authors.initials: AM
authors.lastname: Ray
authors.forename: Dean A
authors.initials: DA
authors.lastname: Rivers
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Trail
authors.forename: David R
authors.initials: DR
authors.lastname: Witty
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008861:Microsomes / Q000187:drug effects; D008956:Models, Chemical; D008968:Molecular Conformation; D020033:Protein Isoforms; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D020033:Protein Isoforms; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A