| Autor: |
de Gaetano, Monica, Tighe, Catherine, Gahan, Kevin, Zanetti, Andrea, Chen, Jianmin, Newson, Justine, Cacace, Antonino, Marai, Mariam, Gaffney, Andrew, Brennan, Eoin, Kantharidis, Phillip, Cooper, Mark E., Leroy, Xavier, Perretti, Mauro, Gilroy, Derek, Godson, Catherine, Guiry, Patrick J. |
| Zdroj: |
Journal of Medicinal Chemistry; July 2021, Vol. 64 Issue: 13 p9193-9216, 24p |
| Abstrakt: |
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)-6significantly 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)-6was investigated. (R)-6activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6were further investigated in vivoin murine models of acute inflammation. Consistent with in vitroobservations, (R)-6attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6in the context of novel inflammatory regulators. |
| Databáze: |
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