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.

Graphical abstractA comparison of in vitro potencies of heterocyclic templates reported as potassium competitive, acid pump antagonists is described. Modification of the more potent 1H-pyrrolo[2,3-c]pyridine to improve in vitro developability properties leading to compound (32) is described.Figure optionsDownload full-size imageDownload as PowerPoint slide