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 35 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 35 improved insulin
resistance.