Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure

This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosedcompound2showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group togenerate atropisomer metabolitesin vitro. In this article, we extended the structure & minus;activity relationship at the C2 position that ledto the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, thepermeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl groupwith a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound21displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robustpharmacodynamic efficacy in the rodent heart failure model. Compound21also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program