This poster describes optimization of a pyrimidinone chemotype of apelin receptor (APJ) agonists culminating in a backup development candidate. From our initial clinical lead <b>1</b>, we explored other heteroaryl scaffolds and discovered pyrimidinone to be a suitable replacement for the hydroxypyridine core. The C2 structure-activity relationship (SAR) was expanded to include substituted cycloalkyl, phenyl and heteroaryl groups. This led to the identification of several potent C2 five-membered heterocycle analogs with excellent metabolic stability. Due to the increased polarity at C2, permeability of the compounds in this series decreased. Further adjustment of polarity by modifying the N1 substituted aryl group and re-optimization for potency of the C5 position led to potent compounds with improved permeability which resulted in the identification of our backup candidate. This candidate displayed excellent pharmacokinetic (PK) profiles in rat, dog and cyno, demonstrated robust pharmacodynamic (PD) efficacy in rodent heart failure (HF) models and also showed an acceptable safety profile in preclinical toxicology studies.

Identification of pyrimidinone amides as potent APJ receptor agonists for the potential treatment of heart failure

ACS Fall 2021

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