Heart Failure (HF) is a condition where the heart cannot pump sufficient blood to maintain normal organ function and remains a critical, unmet medical need. Studies in pre-clinical animal models and in humans have shown that infusion of the peptide [Pyr1]apelin-13 improves cardiac function. [Pyr1]Apelin-13 is an endogenous ligand for the APJ receptor but has a short plasma half-life which has limited the exploration of its therapeutic potential to intravenous and short duration of dosing. Thus, one critical goal in the field has been to discover modalities that are suitable for oral dosing. Several approaches have centered on PK enhanced peptides and peptidomimetics. Our approach was to identify small molecules with potency consistent to that of [Pyr1]apelin-13 with acceptable exposure for oral and chronic dosing. We disclose SAR studies leading to the identification of a lead molecule in the aryldihydroxypyridine series. The lead molecule shares the in vitro activity profile of apelin with oral bioavailability suitable for chronic dosing and was ultimately selected as a clinical candidate.

Identification of a small-molecule agonist for the APJ receptor as a clinical candidate

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.