title: Discovery of a novel small molecule agonist scaffold for the APJ receptor.
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.
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Sanju
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
authors.affiliation: Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Code 6930, 4555 Overlook Avenue SW, Washington, DC 20375, United States.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Deschamps
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bortoff
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Warner
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Vineetha
authors.initials: V
authors.lastname: Vasukuttan
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Decker
authors.affiliation: Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States. Electronic address: srunyon@rti.org.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D002460:Cell Line; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D054852:Small Molecule Libraries; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries
keywords: AGTRL1; APJ small molecule agonist; APLNR; Apelin; Pyrazole