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-LXA 4 -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.

Lipoxins are an important class of pro-resolving mediators that play a crucial role in the resolution of inflammation. Thus, the synthesis of more metabolically stable synthetic lipoxin analogues is an area of significant interest. Herein we report the asymmetric synthesis of lipoxin A4 (LXA4) mimetics in which the triene core of the molecule has been replaced by an aromatic sulfur-containing benzothiophene ring. The key steps in the synthesis included a Friedel-Crafts acylation, a Suzuki coupling between two upper and lower chain fragments, and a highly stereoselective Noyori transfer hydrogenation to set the stereochemistry of the alcohol at the benzylic position. A small library of benzothiophene-containing LXA4 analogues with further structural modifications was also successfully synthesised. These included analogues with phenoxy, p-fluorophenoxy and p-trifluoromethylphenoxy substituents incorporated into the lower alkyl chain of the with the objective of providing enhanced metabolic stability by blocking ω-oxidation pathways.

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