Activation of APJ receptor (APJ-R) by its endogenous peptidic ligand (Pyr1)apelin-13 has demonstrated cardiac function improvement in preclinical animal models and in humans. Due to the short half-life of (Pyr1)apelin-13 in circulation, use in activation of APJ-R has been limited by the need for continuous infusion delivery. To fully explore the therapeutic potential of APJ-R agonism, we targeted the identification of small molecule APJ-R agonists with potency consistent to that of (Pyr1)apelin-13 and with improved exposure profile. In this presentation, the discovery and optimization of two series of small molecule APJ agonists will be discussed. The lead molecule in the biphenyl acid series compared favorably with the endogenous ligand (Pyr1) Apelin-13 in terms of in vitro potency, activation of APJ signaling pathways, and acute in vivo hemodynamic response in rodents. In parallel, SAR development of the aryl hydroxypyrimidinone series led to the identification of potent and orally bioavailable APJ agonists.

Biphenyl acid and aryl hydroxypyrimidinone derivatives as APJ receptor agonists

ACS Spring 2022

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