The APJ receptor (APJ-R) is a class A GPCR that is widely expressed in various tissues, especially in the cardiovascular system including the heart, blood vessels and kidney. Activation of APJ-R by its endogenous ligand (pyr1)apelin-13 demonstrated cardiovascular protective effects in preclinical rodent models. Furthermore, infusion of (pyr1)apelin-13 over 6 hours into healthy volunteers and to patients with heart failure increased ejection fraction and improved cardiac output without significantly affecting blood pressure or heart rate. Since (pyr1)apelin-13 and related peptides exhibit a short half-life in circulation, activation of APJ-R has been limited by continuous infusion delivery. Activation by small molecule agonists with improved exposure profiles is an attractive therapeutic prospect for the chronic treatment of heart failure. The identification and optimization of a series of biphenyl acid based small molecule APJ agonists will be disclosed. The lead molecule in the 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.

Biphenyl acid derivatives as APJ receptor agonists

2019 Spring National Meeting

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