Identification of potent pyrazole based APELIN receptor (APJ) agonists

Abstract

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 (EC50 = 21.5 μM, Ki = 5.2 μM) through focused screening of a compound library, which was further optimized to our initial lead (EC50 = 800 nM, Ki = 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 EC50 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.

Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice

“…However, five-membered closed pyrrolidine ring analogue 5 was However, the 7-azabicyclo[2.2.1]heptane substitution was not tolerated and reduced agonist potency (cAMPi EC 50 = 7562 nM). Interestingly, the seven-membered azepane ring (11) exhibited enhanced agonist potency (cAMPi EC 50 = 181 nM) compared to the cyclohexyl-substituted 2 indicating a preference for seven-membered hydrophobic cycloalkyl ring systems. Overall, fiveor seven-membered cyclic heterocyclic rings (pyrrolidine and azepane) were well-tolerated and exhibited comparable or enhanced agonist potency relative to compound 2.…”

“…36,37 Recently, we discovered and reported a potent pyrazole agonist 2 of the apelin receptor (cAMPi EC 50 = 238 nM, Figure 2) through focused screening, which was further optimized to 3 (cAMPi EC 50 = 97 nM). 11 However, compound 3 was not suitable for in vivo studies since it was rapidly metabolized (human liver microsome stability (HLM) T 1/2 = 6.25 min, CLint = 199 mL/min/kg), had poor solubility (<1 μM at pH 7.4), and was still too lipophilic. A small-molecule agonist that is suitable for in vivo investigation in DIO and possibly in animal models of other diseases modulated by the apelin receptor was needed.…”

Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure

“…As we developed the SAR in this series, there was a literature disclosure of a series of pyrazoles as APJ receptor agonists . We leveraged molecular modeling to help us understand the topology and pharmacophore for binding by overlaying a pyrazole example [( S )-5-cyclohexyl-3-(5-(2,6-dimethoxyphenyl)-1-(4-fluorophenyl)-1 H -pyrazole-3-carboxamido)­pentanoic acid] and compound 3 (Figure ).…”

The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo

“…This is confirmed by the fact it is already commercially available and methods to improve the synthesis of the molecule have been attempted ( Trifonov et al, 2018 ). Furthermore, it has potential as a starting point or stimulus for the development of newer biased small molecule therapeutics at the apelin receptor with improved pharmacokinetic profiles ( Narayanan et al, 2020 ).…”