Abstract
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.
Highlights
The resolution of inflammation is a prerequisite for homeostasis and tissue integrity maintenance,5 and it is understood that chronic, insidious inflammation is an important driver of numerous prevalent conditions including arthritis,6 atherosclerosis, diabetes, and associated vascular complications
The focus has typically been on anti-inflammatory strategies9 and, while these show efficacy, there are challenges regarding the inevitable compromise of innate host defense strategies upon chronic administration
ALX/FPR2, it is evident that activation by the mimetic was significantly (p < 0.05) 40% lower than that induced by the native LXA4 (Figure 11)
Summary
Inflammation is a vital physiological response to infection or trauma. Implicit in effective inflammation is a response limited in time and space and coupled to repair, which promotes return to homeostasis (catabasis). In contrast, unresolved chronic inflammation leads to fibrosis, tissue scarring, and, organ failure. The resolution of inflammation is a prerequisite for homeostasis and tissue integrity maintenance, and it is understood that chronic, insidious inflammation is an important driver of numerous prevalent conditions including arthritis, atherosclerosis, diabetes, and associated vascular complications. Efforts to repurpose existing drugs and to develop new ones for the treatment of such diseases are ongoing. To date, the focus has typically been on anti-inflammatory strategies and, while these show efficacy, there are challenges regarding the inevitable compromise of innate host defense strategies upon chronic administration.. Both mimetics from group D, (R)- and (S)-8, significantly attenuating (p < 0.05−0.0001) IFNγ release, did not perform better than the parent compound (negative PD scores) (Figure S3). A postanalysis “safety study” was conducted on all QNX-sLXms. For each tested compound, we calculated an in vitro “Safety index” (Si) by relating its “anti-inflammatory half-maximal activity” (the highest dose among the IC50 of the extrinsic LPSchallenged phenotype: NF-κB activity, proinflammatory cytokine, and LDH release) to its intrinsic “toxicity” (expressed as the relative half-maximal LDH-associated cytotoxicity). The lead compound tested for cytotoxicity displayed safety within the pM to nM range, in the presence or absence of LPS Given the impact on inflammatory responses reported above, subsequent in vitro and in vivo investigations are detailed for (R)-
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