Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate
James A. Johnson, Soong‐Hoon Kim, Jiang Ji, Monique Phillips, William A. Schumacher, Jeffrey S. Bostwick, Peter S. Gargalovic, Joelle M. Onorato, Chiuwa E. Luk, Claudia Generaux, Yan He, Xueqing Chen, Carrie Xu, Michael A. Galella, Tao Wang, David A. Gordon, Ruth R. Wexler, Heather J. Finlay
Abstract
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.