Department of Chemistry and Biochemistry and BioFrontiers Institute, 596 University of Colorado at Boulder, Boulder, CO 80309-0596, USA.
Bioorg Med Chem. 2012 Oct 15;20(20):6073-9. doi: 10.1016/j.bmc.2012.08.022. Epub 2012 Aug 25.
Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g., TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.
抑制 TLR4 信号转导是干预几种促炎疾病病因的重要治疗策略。近年来，人们进行了大量研究，旨在探索这一策略，并确定 TLR4 途径的小分子抑制剂。然而，最近一些针对 TLR4 信号的先进候选药物（如 TAK242 和 Eritoran）的失败促使我们继续寻找新的化学结构来抑制这一关键的炎症反应途径。在这里，我们通过基于细胞的筛选报告了一组新的 TLR4 信号抑制剂的鉴定。合成了一系列芳基烯丙基丙二酸盐类似物，并在鼠巨噬细胞中检测它们对 LPS 诱导的一氧化氮 (NO) 产生的抑制活性。发现先导化合物 1（NCI126224）在纳摩尔-低微摩尔范围内抑制 LPS 诱导的核因子-κB（NF-κB）、肿瘤坏死因子 (TNF-α)、白细胞介素-1β (IL-1β) 和一氧化氮 (NO) 的产生。总之，这项研究表明 1 是治疗各种炎症性疾病的有前途的潜在治疗候选物。
