School of Medicine, Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin D04 N2E5, Ireland.
Centre for Synthesis and Chemical Biology, School of Chemistry, UCD Conway Institute, University College Dublin, Belfield, Dublin D04 N2E5, Ireland.
J Med Chem. 2021 Jul 8;64(13):9193-9216. doi: 10.1021/acs.jmedchem.1c00403. Epub 2021 Jun 17.
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-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that ()- (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. ()- 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 ()- was investigated. ()- activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of ()- were further investigated in murine models of acute inflammation. Consistent with observations, ()- attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm ()- in the context of novel inflammatory regulators.
炎症反应的持续存在是许多常见疾病的基础。最近的研究发现，脂质介质（以脂氧素（LXs）为代表）是炎症反应消退的驱动因素，这提示了其潜在的治疗益处。我们报告了新型含喹喔啉的合成 LXA 模拟物（QNX-sLXms）的不对称制备方法。筛选了 8 种新型化合物对炎症反应的影响。构效关系（SAR）研究表明，（）-（也称为 AT-02-CT）是测试中最有效和最有效的抗炎化合物。（）-显著抑制单核细胞和血管平滑肌细胞中脂多糖（LPS）和肿瘤坏死因子-α（TNF-α）诱导的 NF-κB 活性。研究了（）-的分子靶标。（）-激活内源性 LX 受体甲酰肽受体 2（ALX/FPR2）。在急性炎症的小鼠模型中进一步研究了（）-的抗炎特性。与观察结果一致，（）-减轻了炎症反应。这些结果支持了新型炎症调节剂中先导 QNX-sLXm（）-的治疗潜力。
