Saccharin Derivatives as Inhibitors of Interferon-Mediated Inflammation
Saccharin Derivatives as Inhibitors of Interferon-Mediated Inflammation
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DOI：
10.1021/jm500409k
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发表时间：
2014-06-26
影响因子：
7.3
通讯作者：
Yin, Hang
中科院分区：
文献类型：
--
作者：
Csakai, Adam;Smith, Christina;Yin, Hang
已经鉴定了一系列新的基于糖精的干扰素信号通路拮抗剂。通过体外高通量筛选与科罗拉多中心药物发现（C2 D2）试点图书馆，我们确定了命中化合物1，这是广泛的结构-活性关系研究的基础。我们的努力产生了一种先导抗炎化合物，N-（呋喃-2-基甲基）-N-{4-[（1，1，3-三氧代-2，3-二氢-1 λ（6），2-苯并噻唑-2-基）甲基]苯甲酰基}氨基甲酸叔丁酯CU-CPD 103（103），其使用已建立的一氧化氮（NO）信号传导测定作为有效抑制剂。随着对其抑制机制的进一步研究，我们证明了103通过JAK/STAT 1途径进行这种抑制，为可能的治疗用途提供了药物样小分子炎症抑制剂。
A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure-activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1 lambda(6),2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay. With further studies of its inhibitory mechanisms, we demonstrated that 103 carries out this inhibition through the JAK/STAT1 pathway, providing a drug-like small molecule inflammation suppressant for possible therapeutic uses.