Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms)
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Volume
64
Pagination
9193 - 9216
Publisher
Publisher URL
DOI
10.1021/acs.jmedchem.1c00403
Journal
JOURNAL OF MEDICINAL CHEMISTRY
Issue
ISSN
0022-2623
Metadata
Show full item recordAbstract
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 syntheticLXA4-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.