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Identification of Potent Pyrazole‐Based Biased Small Molecule APJ Receptor Agonists
Author(s) -
Narayanan Sanju,
Vasukuttan Vineetha,
Rajagopal Sudarshan,
Maitra Rangan,
Runyon Scott P
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.670.13
Subject(s) - pyrazole , receptor , in vivo , chemistry , agonist , small molecule , functional selectivity , pharmacology , computational biology , partial agonist , in vitro , stereochemistry , biochemistry , combinatorial chemistry , biology , microbiology and biotechnology
The apelinergic system comprises the APJ receptor and its cognate apelin and ELABELA peptides of various lengths. This system has become an increasingly attractive target for cardiometabolic diseases. However, in vivo studies of this receptor are difficult because endogenous peptides are labile with short half‐lives and small molecule ligands are under reported. Recently, we discovered a novel pyrazole based small molecule agonist of APJ (EC 50 = 21.5 μM, K i = 5.2 μM) through focused screening of a compound library, which was further optimized to our initial lead (EC 50 = 800 nM, K i = 1.3 μM). In our efforts to synthesize more potent agonists and to explore the structural features important for APJ agonism, we carried out structural modifications at the pyrazole core as well as the amino acid side‐chain of our initial lead. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC 50 values of ~100 nM using separate calcium mobilization and cAMP generation functional assays. Recruitment of β‐arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β‐arrestin recruitment. These compounds may be suitable for chronic in vivo studies of APJ and await additional characterization. Support or Funding Information NIH Grants: 1R01HD079547‐01A1 and 1R01DK103625‐01A1 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .