Functional antagonists of the Apelin (APJ) receptor

Abstract

The recently discovered apelin receptor (APJ, AGTRL-1, APLNR) system has emerged as a critical mediator of cardiovascular homeostasis involved in the pathogenesis of hypertension, heart failure, atherosclerosis and other cardiovascular diseases. Herein is presented the discovery and characterization the first non-peptide based potent (3.7 μM) small molecule APJ functional agonist in cell-based assays, that is >21 fold selective over the closely related angiotensin 1 (AT1) receptor, derived from a high throughput screen (HTS) of the ~330,600 compound Molecular Libraries Small Molecule Repository (MLSMR) collection. This agonist showed some binding activity against 4 out of 37 other GPCRs and transporters, including the 5-HT1A, α2C adrenergic, and benzylpiperazine receptors (55%I, 51%I and 65%I at 10 μM, respectively) and the norepinephrine transporter (57%I at 10 μM). The synthetic methodology, development of structure-activity relationships (SAR), and initial in vitro pharmacologic characterization are also presented. This probe molecule provides a useful tool compound for investigators interested in understanding apelin receptor pharmacology and function.