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.
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.
Westaway
Susan M
SM
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
Brown
Samantha L
SL
Fell
Stephen C M
SC
Johnson
Christopher N
CN
MacPherson
David T
DT
Mitchell
Darren J
DJ
Myatt
James W
JW
Stanway
Steven J
SJ
Seal
Jon T
JT
Stemp
Geoffrey
G
Thompson
Mervyn
M
Lawless
Kirk
K
McKay
Fiona
F
Muir
Alison I
AI
Barford
Jonathan M
JM
Cluff
Chermaine
C
Mahmood
Sadhia R
SR
Matthews
Kim L
KL
Mohamed
Shiyam
S
Smith
Beverley
B
Stevens
Alexander J
AJ
Bolton
Victoria J
VJ
Jarvie
Emma M
EM
Sanger
Gareth J
GJ
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*
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