Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate

• Published in: Journal of medicinal chemistry 2021-03, Vol.64 (6), p.3086-3099
• Main Authors: Johnson, James A, Kim, Soong-Hoon, Jiang, Ji, Phillips, Monique, Schumacher, William A, Bostwick, Jeffrey S, Gargalovic, Peter S, Onorato, Joelle M, Luk, Chiuwa E, Generaux, Claudia, He, Yan, Chen, Xue-Qing, Xu, Carrie, Galella, Michael A, Wang, Tao, Gordon, David A, Wexler, Ruth R, Finlay, Heather J
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01878

Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches. We sought a small-molecule APJ receptor agonist approach to target a compound with a pharmacokinetic profile amenable for chronic oral administration. This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure–volume loop model and was advanced as a clinical candidate.