Development of Central Nervous System-Penetrant Apelin Receptor Agonists

The apelinergic system comprises the peptidergic GPCR apelin receptor (APLNR) and two distinct classes of endogenous peptides called apelin and ELA/Apela. Regulation of the apelinergic system is a promising therapeutic approach for insulin resistance associated with metabolic syndrome. While small-molecule agonists of the apelin receptor have been described previously, well-characterized central nervous system (CNS)-penetrant compounds are needed. Herein, we describe the discovery and characterization of a novel set of pyrazole- and imidazole-based APLNR agonists. Of these, the imidazole <b>35</b> was identified as a potent, CNS-penetrant biased agonist of APLNR with significant bias (∼8-fold) for G-protein over β-arrestin 2 signaling. This compound is orally active with good pharmacokinetic properties. Treatment of obese diabetic mice with <b>35</b> improved insulin resistance.