Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms)
| Autor: | Catherine Tighe, Monica de Gaetano, Andrea Zanetti, Catherine Godson, Jianmin Chen, Patrick J. Guiry, Mark E. Cooper, Xavier Leroy, Kevin Gahan, Eoin P. Brennan, Derek W. Gilroy, Antonino Cacace, Mauro Perretti, Mariam Marai, Justine Newson, Andrew Gaffney, Phillip Kantharidis |
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| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Lipopolysaccharide Cell Survival Drug Evaluation Preclinical Context (language use) Inflammation Pharmacology 01 natural sciences Article Monocytes Formyl peptide receptor 2 Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound In vivo Quinoxalines Drug Discovery medicine Animals Humans Receptors Lipoxin Receptor Cells Cultured 030304 developmental biology 0303 health sciences Lipoxin Dose-Response Relationship Drug Molecular Structure Tumor Necrosis Factor-alpha Anti-Inflammatory Agents Non-Steroidal NF-kappa B Receptors Formyl Peptide In vitro 0104 chemical sciences 3. Good health 010404 medicinal & biomolecular chemistry chemistry Molecular Medicine medicine.symptom |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00403 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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