Identification of 6-Hydroxypyrimidin-4(1 H )-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. (Pyr ¹ )apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr ¹ )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 (Pyr ¹ )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(1 H )-one-3-carboxamide 14a with pharmacodynamic effects comparable to those of compound 1 .
Competing Interests: The authors declare the following competing financial interest(s): The authors of this Letter were employees of Bristol Myers Squibb at the time of this research.
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