Identification of 6‑Hydroxypyrimidin-4(1H)‑one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists

The apelin receptor (APJ) is a significant regulator of cardiovascular function and is involved in heart failure and other cardiovascular diseases. (Pyr¹)­apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr¹)­apelin-13 increases cardiac output in preclinical models and humans. Recently we disclosed clinical lead BMS-986224 (1), a C3 oxadiazole pyridinone APJ receptor agonist with robust pharmacodynamic effects similar to (Pyr¹)­apelin-13 in an acute rat pressure–volume loop model. Herein we describe the structure–activity relationship of the carboxamides as oxadiazole bioisosteres at C3 of the pyridinone core and C5 of the respective pyrimidinone core. This study led to the identification of structurally differentiated 6-hydroxypyrimidin-4­(1H)-one-3-carboxamide 14a with pharmacodynamic effects comparable to those of compound 1.