Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4Mimetics (QNX-sLXms)

Monica De Gaetano, Catherine Tighe, Kevin Gahan, Andrea Zanetti, Jianmin Chen, Justine Newson, Antonino Cacace, Mariam Marai, Andrew Gaffney, Eoin Brennan, Phillip Kantharidis, Mark E. Cooper, Xavier Leroy, Mauro Perretti, Derek Gilroy, Catherine Godson, Patrick J. Guiry

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14 Citations (Scopus)


Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

Original languageEnglish
Pages (from-to)9193-9216
Number of pages24
JournalJournal of Medicinal Chemistry
Issue number13
Publication statusPublished - 8 Jul 2021

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