1区 · 医学
Article
作者: Schumacher, William A. ; He, Yan ; Xu, Carrie ; Gargalovic, Peter S. ; Gordon, David A. ; Wang, Tao ; Finlay, Heather J. ; Wexler, Ruth R. ; Galella, Michael A. ; Kim, Soong-Hoon ; Jiang, Ji ; Phillips, Monique ; Bostwick, Jeffrey S. ; Onorato, Joelle M. ; Johnson, James A. ; Luk, Chiuwa E. ; Generaux, Claudia ; Chen, Xue-Qing
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.