The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
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
Conway
Elizabeth
E
Heightman
Tom D
TD
Johnson
Christopher N
CN
Lapsley
Kate
K
Macdonald
Gregor J
GJ
MacPherson
David T
DT
Mitchell
Darren J
DJ
Myatt
James W
JW
Seal
Jon T
JT
Stanway
Steven J
SJ
Stemp
Geoffrey
G
Thompson
Mervyn
M
Celestini
Paolo
P
Colombo
Andrea
A
Consonni
Alessandra
A
Gagliardi
Stefania
S
Riccaboni
Mauro
M
Ronzoni
Silvano
S
Briggs
Michael A
MA
Matthews
Kim L
KL
Stevens
Alexander J
AJ
Bolton
Victoria J
VJ
Boyfield
Izzy
I
Jarvie
Emma M
EM
Stratton
Sharon C
SC
Sanger
Gareth J
GJ
D000818:Animals; D002244:Carbon / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D005755:Gastrins / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000737:chemistry; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000737:chemistry
C540149:GSK326416; D005755:Gastrins; D011725:Pyridines; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D002244:Carbon