Discovery of 3-(Indol-5-yl)-indazole Derivatives as Novel Myeloid Differentiation Protein 2/Toll-like Receptor 4 Antagonists for Treatment of Acute Lung Injury
Discovery of 3-(Indol-5-yl)-indazole Derivatives as Novel Myeloid Differentiation Protein 2/Toll-like Receptor 4 Antagonists for Treatment of Acute Lung Injury
复制标题
发现 3-(吲哚-5-基)-吲唑衍生物作为新型骨髓分化蛋白 2/Toll 样受体 4 拮抗剂用于治疗急性肺损伤
DOI：
10.1021/acs.jmedchem.9b00316
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发表时间：
2019-06-13
影响因子：
7.3
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Liu, Zhiguo;Chen, Lingfeng;Liang, Guang
Acute lung injury (ALI) is often caused by systemic inflammatory responses. Targeting the myeloid differentiation protein 2/toll-like receptor 4 (MD2 TLR4) complex may be a promising way to treat Gram-negative bacterial-induced inflammatory disorders. In this study, we report the design and synthesis of a new series of 3-(indo1-5-yl)-indazoles, which were evaluated for their anti-inflammatory activities in macrophages. Among the analogues generated, the promising 3-(indol-5-yl)-indazole analogue 22m inhibited lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in macrophages with IC50 values of 0.89 and 0.53 mu M, respectively. Compound 22m was then identified as an MD2-TLR4 antagonist in suppressing LPS-induced inflammatory responses. In vivo administration of 22m significantly inhibited macrophage infiltration and ameliorated histopathological changes in lung tissues of LPS-challenged mice. Our studies have identified a new 3-(indol-5-yl)-indazole, 22m, as a potent MD2-TLR4 inhibitor and lay the groundwork for future drug development of anti-inflammatory agents for the treatment of ALI.
