title: Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.
abstract: This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
authors.affiliation: GlaxoSmithKline R&D, Neurology Centre of Excellence for Drug Discovery, Harlow, Essex CM19 5AW, United Kingdom. Electronic address: David.M.Wilson@astrazeneca.com.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: James
authors.initials: J
authors.lastname: Apps
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bailey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bamford
authors.forename: Isabel J
authors.initials: IJ
authors.lastname: Beresford
authors.forename: Kim
authors.initials: K
authors.lastname: Brackenborough
authors.forename: Michael A
authors.initials: MA
authors.lastname: Briggs
authors.forename: Stephen
authors.initials: S
authors.lastname: Brough
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Calver
authors.forename: Barry
authors.initials: B
authors.lastname: Crook
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Davis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Davis
authors.forename: Susannah
authors.initials: S
authors.lastname: Davis
authors.forename: David K
authors.initials: DK
authors.lastname: Dean
authors.forename: Leanne
authors.initials: L
authors.lastname: Harris
authors.forename: Teresa
authors.initials: T
authors.lastname: Heslop
authors.forename: Vicky
authors.initials: V
authors.lastname: Holland
authors.forename: Phillip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Terrance A
authors.initials: TA
authors.lastname: Panchal
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Parr
authors.forename: Nigel
authors.initials: N
authors.lastname: Quashie
authors.forename: Joanne
authors.initials: J
authors.lastname: Schogger
authors.forename: Sanjeet S
authors.initials: SS
authors.lastname: Sehmi
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Jon G A
authors.initials: JG
authors.lastname: Steadman
authors.forename: Brenda
authors.initials: B
authors.lastname: Trail
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wald
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Takle
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D006207:Half-Life; D000882:Haplorhini; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; C584220:GSK239512; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide
keywords: Clinical candidate; GPCR; H(3) receptor; Histamine; Lead optimisation; Neurotransmitters; Receptor antagonists