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....

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Published inBioorganic & medicinal chemistry letters Vol. 73; p. 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 Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 01.10.2022
Elsevier
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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.
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.128882