2. Academic Validation
  3. Functional Agonists of the Apelin (APJ) Receptor

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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