title: Discovery of biaryl inhibitors of H+/K+ ATPase.
abstract: We report the identification of a novel biaryl template for H(+)/K(+) ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.
authors.affiliation: GlaxoSmithKline, Medicinal Chemistry, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Neil.S.Garton@gsk.com
authors.forename: Neil
authors.initials: N
authors.lastname: Garton
authors.forename: Nick
authors.initials: N
authors.lastname: Bailey
authors.forename: Mark
authors.initials: M
authors.lastname: Bamford
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Demont
authors.forename: Irene
authors.initials: I
authors.lastname: Farre-Gutierrez
authors.forename: Gail
authors.initials: G
authors.lastname: Hutley
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Bravi
authors.forename: Paula
authors.initials: P
authors.lastname: Pickering
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D054328:Proton Pump Inhibitors; D017506:H(+)-K(+)-Exchanging ATPase