Design and preparation of N-linked hydroxypyridine-based APJ agonists.

Abstract

Agonism of the apelin receptor (APJ) has demonstrated beneficial effects in models of heart failure. We have previously disclosed compounds such as 4, which showed good APJ agonist activity but were metabolized to the mono-demethylated, non-interconverting atropisomer metabolites. Herein, we detail the design and optimization of a novel series of N-linked APJ agonists with good potency, metabolic stability, and rat pharmacokinetic profile, which are unable to undergo the same metabolic mono-demethylation cleavage.

• Authors: Jeremy M Richter, J Alex Bates, Peter Gargalovic, Joelle M Onorato, Claudia Generaux, Tao Wang, David A Gordon, Ruth R Wexler, Heather J Finlay
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 73 Pg. 128882 (10 01 2022) ISSN: 1464-3405 [Electronic] England
• PMID: 35817293 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Apelin
• Apelin Receptors
• Pyridines
• Receptors, G-Protein-Coupled
• hydroxypyridines

Topics

• Animals
• Apelin
• Apelin Receptors (agonists)
• Pyridines
• Rats
• Receptors, G-Protein-Coupled (agonists)