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

Authors :
Richter JM
Alex Bates J
Gargalovic P
Onorato JM
Generaux C
Wang T
Gordon DA
Wexler RR
Finlay HJ
Source :
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Oct 01; Vol. 73, pp. 128882. Date of Electronic Publication: 2022 Jul 08.
Publication Year :
2022

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.<br /> (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1464-3405
Volume :
73
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
35817293
Full Text :
https://doi.org/10.1016/j.bmcl.2022.128882