Evaluation of basic, heterocyclic ring systems as templates for use as potassium competitive acid blockers (pCABs).
A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic optimisation. Modifications were carried out to improve the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and comparable to the clinically efficacious AZD-0865.
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, Harlow, Essex CM19 5AW, United Kingdom. Terry.A.Panchal@gsk.com
Terry
T
Panchal
Nick
N
Bailey
Mark
M
Bamford
Emmanuel
E
Demont
Richard
R
Elliott
Irene
I
Farre-Gutierrez
Neil
N
Garton
Thomas
T
Hayhow
Gail
G
Hutley
Antoinette
A
Naylor
D001667:Binding, Competitive; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D054328:Proton Pump Inhibitors; D011725:Pyridines