Biphenyl Acid Derivatives as APJ Receptor Agonists

The APJ receptor and its endogenous peptidic ligand apelin
have
been implicated as important modulators of cardiovascular function,
and APJ receptor agonists may be beneficial in the treatment of heart
failure. In this article, we describe the discovery of a series of
biphenyl acid derivatives as potent APJ receptor agonists. Following
the identification of initial high-throughput screen lead 2, successive optimization led to the discovery of lead compound 15a. Compound 15a demonstrated comparable in
vitro potency to apelin-13, the endogenous peptidic ligand for the
APJ receptor. In vivo, compound 15a demonstrated a dose-dependent
improvement in the cardiac output in male Sprague Dawley rats with
no significant changes in either mean arterial blood pressure or heart
rate, consistent with the hemodynamic profile of apelin-13 in an acute
pressure volume loop model.