Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs).
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.
Bailey
Nick
N
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Bamford
Mark J
MJ
Brissy
Delphine
D
Brookfield
Joanna
J
Demont
Emmanuel
E
Elliott
Richard
R
Garton
Neil
N
Farre-Gutierrez
Irene
I
Hayhow
Thomas
T
Hutley
Gail
G
Naylor
Antoinette
A
Panchal
Terry A
TA
Seow
Hui-Xian
HX
Spalding
David
D
Takle
Andrew K
AK
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D054328:Proton Pump Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D054328:Proton Pump Inhibitors; D011725:Pyridines; D017506:H(+)-K(+)-Exchanging ATPase; C001439:imidazo(1,2-a)pyridine