Discovery of biaryl inhibitors of H+/K+ ATPase.
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.
Garton
Neil
N
GlaxoSmithKline, Medicinal Chemistry, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Neil.S.Garton@gsk.com
Bailey
Nick
N
Bamford
Mark
M
Demont
Emmanuel
E
Farre-Gutierrez
Irene
I
Hutley
Gail
G
Bravi
Gianpaolo
G
Pickering
Paula
P
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
D007093:Imidazoles; D054328:Proton Pump Inhibitors; D017506:H(+)-K(+)-Exchanging ATPase