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

[Display omitted] 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....

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2022-10, Vol.73, p.128882-128882, Article 128882
Main Authors: Richter, Jeremy M., Alex Bates, J., Gargalovic, Peter, Onorato, Joelle M., Generaux, Claudia, Wang, Tao, Gordon, David A., Wexler, Ruth R., Finlay, Heather J.
Format: Article
Language:English
Subjects:
Apelin
APJ
Heart failure
Hydroxypyridine
Small molecule
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.128882