2. Academic Validation
  3. Discovery of a novel small molecule agonist scaffold for the APJ receptor

Discovery of a novel small molecule agonist scaffold for the APJ receptor

  • Bioorg Med Chem. 2016 Aug 15;24(16):3758-70. doi: 10.1016/j.bmc.2016.06.018.
Sanju Narayanan 1,  Rangan Maitra 1,  Jeffery R Deschamps 2,  Katherine Bortoff 1,  James B Thomas 1,  Yanyan Zhang 1,  Keith Warner 1,  Vineetha Vasukuttan 1,  Ann Decker 1,  Scott P Runyon 3
Affiliations

Affiliations

  • 1 Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
  • 2 Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Code 6930, 4555 Overlook Avenue SW, Washington, DC 20375, United States.
  • 3 Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States. Electronic address: srunyon@rti.org.
PMID: 27369451 DOI: 10.1016/j.bmc.2016.06.018
Abstract

The apelinergic system includes a series of endogenous Peptides apelin, ELABELA/TODDLER and their 7-transmembrane G-protein coupled apelin receptor (APJ, AGTRL-1, APLNR). The APJ receptor is an attractive therapeutic target because of its involvement in cardiovascular diseases and potentially Other disorders including liver fibrosis, obesity, diabetes, and neuroprotection. To date, pharmacological characterization of the APJ receptor has been limited due to the lack of small molecule functional agonists or antagonists. Through focused screening we identified a drug-like small molecule agonist hit 1 with a functional EC50 value of 21.5±5μM and binding affinity (Ki) of 5.2±0.5μM. Initial structure-activity studies afforded compound 22 having a 27-fold enhancement in potency and the first sub-micromolar full agonist with an EC50 value of 800±0.1nM and Ki of 1.3±0.3μM. Preliminary SAR, synthetic methodology, and in vitro pharmacological characterization indicate this scaffold will serve as a favorable starting point for further refinement of APJ potency and selectivity.

Keywords

AGTRL1; APJ small molecule agonist; APLNR; Apelin; Pyrazole.

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