title: Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate.
abstract: N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
authors.affiliation: Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK. sue.m.westaway@gsk.com
authors.forename: Susan M
authors.initials: SM
authors.lastname: Westaway
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Brown
authors.forename: Stephen C M
authors.initials: SC
authors.lastname: Fell
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: David T
authors.initials: DT
authors.lastname: MacPherson
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: James W
authors.initials: JW
authors.lastname: Myatt
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stanway
authors.forename: Jon T
authors.initials: JT
authors.lastname: Seal
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: Mervyn
authors.initials: M
authors.lastname: Thompson
authors.forename: Kirk
authors.initials: K
authors.lastname: Lawless
authors.forename: Fiona
authors.initials: F
authors.lastname: McKay
authors.forename: Alison I
authors.initials: AI
authors.lastname: Muir
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Barford
authors.forename: Chermaine
authors.initials: C
authors.lastname: Cluff
authors.forename: Sadhia R
authors.initials: SR
authors.lastname: Mahmood
authors.forename: Kim L
authors.initials: KL
authors.lastname: Matthews
authors.forename: Shiyam
authors.initials: S
authors.lastname: Mohamed
authors.forename: Beverley
authors.initials: B
authors.lastname: Smith
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Bolton
authors.forename: Emma M
authors.initials: EM
authors.lastname: Jarvie
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Sanger
mesh_terms: D000818:Animals; D004285:Dogs; D055808:Drug Discovery; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011706:Pyloric Antrum / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018013:Receptors, Neuropeptide / Q000819:agonists*
chemical_list: D005765:Gastrointestinal Agents; C541863:N-(3-fluorophenyl)-1-((4-(((3S)-3-methyl-1-piperazinyl)methyl)phenyl)acetyl)-4-piperidinamine; D010879:Piperazines; D010880:Piperidines; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor