title: Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs).
abstract: 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.
authors.affiliation: Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: Bailey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bamford
authors.forename: Delphine
authors.initials: D
authors.lastname: Brissy
authors.forename: Joanna
authors.initials: J
authors.lastname: Brookfield
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Demont
authors.forename: Richard
authors.initials: R
authors.lastname: Elliott
authors.forename: Neil
authors.initials: N
authors.lastname: Garton
authors.forename: Irene
authors.initials: I
authors.lastname: Farre-Gutierrez
authors.forename: Thomas
authors.initials: T
authors.lastname: Hayhow
authors.forename: Gail
authors.initials: G
authors.lastname: Hutley
authors.forename: Antoinette
authors.initials: A
authors.lastname: Naylor
authors.forename: Terry A
authors.initials: TA
authors.lastname: Panchal
authors.forename: Hui-Xian
authors.initials: HX
authors.lastname: Seow
authors.forename: David
authors.initials: D
authors.lastname: Spalding
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Takle
mesh_terms: 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
chemical_list: D054328:Proton Pump Inhibitors; D011725:Pyridines; D017506:H(+)-K(+)-Exchanging ATPase; C001439:imidazo(1,2-a)pyridine