title: The discovery of the benzazepine class of histamine H3 receptor antagonists.
abstract: This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
authors.affiliation: GlaxoSmithKline R&D, Neurology CEDD, 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: Michael A
authors.initials: MA
authors.lastname: Briggs
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Calver
authors.forename: Barry
authors.initials: B
authors.lastname: Crook
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: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: Terry
authors.initials: T
authors.lastname: Panchal
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Parr
authors.forename: Nigel
authors.initials: N
authors.lastname: Quashie
authors.forename: Jon G A
authors.initials: JG
authors.lastname: Steadman
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: Andrew K
authors.initials: AK
authors.lastname: Takle
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Trail
authors.forename: Trevor
authors.initials: T
authors.lastname: White
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins; D019389:Cytochrome P-450 CYP2D6
keywords: Alzheimer’s disease; Benzazepine; GPCR; H(3) receptor antagonist; Histamine; Neurotransmitters