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

Jeremy M Richter; J Alex Bates; Peter Gargalovic; Joelle M Onorato; Claudia Generaux; Tao Wang; David A Gordon; Ruth R Wexler; Heather J Finlay

doi:10.1016/j.bmcl.2022.128882

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

Bioorg Med Chem Lett. 2022 Oct 1:73:128882. doi: 10.1016/j.bmcl.2022.128882. Epub 2022 Jul 8.

Authors

Jeremy M Richter¹, J Alex Bates², Peter Gargalovic², Joelle M Onorato², Claudia Generaux², Tao Wang², David A Gordon², Ruth R Wexler², Heather J Finlay²

Affiliations

¹ Bristol-Myers Squibb Research & Early Development, Princeton, NJ 08540, USA. Electronic address: [email protected].
² Bristol-Myers Squibb Research & Early Development, Princeton, NJ 08540, USA.

PMID: 35817293
DOI: 10.1016/j.bmcl.2022.128882

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.

Keywords: APJ; Apelin; Heart failure; Hydroxypyridine; Small molecule.

MeSH terms

Animals
Apelin
Apelin Receptors / agonists
Pyridines*
Rats
Receptors, G-Protein-Coupled* / agonists

Substances

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