posted on 2021-06-17, 16:37authored byMonica 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
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.