Functional Agonists of the Apelin (APJ) Receptor

Pasha Khan ,  Patrick R Maloney ,  Michael Hedrick ,  Palak Gosalia ,  Monika Milewski ,  Linda Li ,  Gregory P Roth ,  Eduard Sergienko ,  Eigo Suyama ,  Eliot Sugarman ,  Kevin Nguyen ,  Alka Mehta ,  Stefan Vasile ,  Ying Su ,  Shenghua Shi ,  Derek Stonich ,  Hung Nguyen ,  Fu-Yue Zeng ,  Arianna Mangravita Novo ,  Michael Vicchiarelli ,  Jena Diwan ,  Thomas DY Chung ,  Anthony B Pinkerton ,  Layton H Smith
PMID: 22834038
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.

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