2. Academic Validation
  3. Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms)

Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms)

  • J Med Chem. 2021 Jul 8;64(13):9193-9216. doi: 10.1021/acs.jmedchem.1c00403.
Monica de Gaetano 1,  Catherine Tighe 2,  Kevin Gahan 2,  Andrea Zanetti 2,  Jianmin Chen 3,  Justine Newson 4,  Antonino Cacace 1,  Mariam Marai 1,  Andrew Gaffney 1,  Eoin Brennan 1,  Phillip Kantharidis 5,  Mark E Cooper 5,  Xavier Leroy 6,  Mauro Perretti 3,  Derek Gilroy 4,  Catherine Godson 1,  Patrick J Guiry 2
Affiliations

Affiliations

  • 1 School of Medicine, Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin D04 N2E5, Ireland.
  • 2 Centre for Synthesis and Chemical Biology, School of Chemistry, UCD Conway Institute, University College Dublin, Belfield, Dublin D04 N2E5, Ireland.
  • 3 William Harvey Research Institute, Queen Mary University London, London EC1M 6BQ, U.K.
  • 4 Centre for Clinical Pharmacology, University College London, London WC1E 6JF, U.K.
  • 5 Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
  • 6 Domain Therapeutics SA, 67400 Strasbourg, Illkirch, France.
PMID: 34138563 DOI: 10.1021/acs.jmedchem.1c00403
Abstract

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.

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