NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease.
NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease.
复制标题
NS6180 是一种新型 K(Ca) 3.1 通道抑制剂，可预防炎症性肠病大鼠模型中的 T 细胞活化和炎症。
DOI：
10.1111/j.1476-5381.2012.02143.x
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发表时间：
2013
影响因子：
7.3
通讯作者：
Christophersen,P
中科院分区：
文献类型：
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作者：
Strøbæk,D;Brown,DT;Jenkins,DP;Chen,Y-J;Coleman,N;Ando,Y;Chiu,P;Jørgensen,S;Demnitz,J;Wulff,H;Christophersen,P
背景与目的KCa 3.1通道是治疗免疫性疾病的潜在靶点。我们从KCa 3.1抑制剂的新化学类别中鉴定了一种化合物，并在体外和体内评估了免疫应答的抑制作用。（4-[[3-（三氟甲基）苯基]甲基]-2H-1，4-苯并噻嗪-3（4 H）-酮）在KCa3.1通道上的效力和分子作用位点、对其他靶点的选择性方面，NS 6180对T细胞活化以及2，4-二硝基苯磺酸诱导的结肠炎（炎症性肠病（IBD）大鼠模型）的药代动力学和炎症控制的影响。Key ResultsNS 6180抑制克隆的人KCa 3.1通道（IC 50 = 9 nM）通过T250和V275，相同的氨基酸残基赋予对三芳基甲烷的敏感性，如TRAM-34。NS 6180抑制人、小鼠和大鼠红细胞中内源性表达的KCa 3.1通道，效力相似（15-20 nM）。NS 6180在亚微米浓度下抑制大鼠和小鼠脾细胞增殖，并有效抑制IL-2和IFN-γ的产生，而对IL-4和TNF-α的影响较小，对IL-17的产生没有影响。抗体染色显示健康结肠中的KCa 3.1通道和诱导结肠炎后与浸润免疫细胞相关的强烈上调。尽管血浆暴露较差，但NS 6180（3和10 mg·kg− 1b.i.d.）抑制结肠炎症和改善体重增加的效果与标准IBD药物柳氮磺胺吡啶（300 mg·kg-1 q.d.）相同。结论和启示NS 6180代表一类新的KCa3.1通道抑制剂，抑制实验性结肠炎，提示KCa3.1通道作为药物控制肠道炎症的目标。
Background and PurposeThe KCa3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of KCa3.1 inhibitors and assessedin vitroandin vivoinhibition of immune responses.Experimental ApproachWe characterized the benzothiazinone NS6180 (4‐[[3‐(trifluoromethyl)phenyl]methyl]‐2H‐1,4‐benzothiazin‐3(4H)‐one) with respect to potency and molecular site of action on KCa3.1 channels, selectivity towards other targets, effects on T‐cell activation as well as pharmacokinetics and inflammation control in colitis induced by 2,4‐dinitrobenzene sulfonic acid, a rat model of inflammatory bowel disease (IBD).Key ResultsNS6180 inhibited cloned human KCa3.1 channels (IC50= 9 nM) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM‐34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15–20 nM). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL‐2 and IFN‐γ production, while exerting smaller effects on IL‐4 and TNF‐α and no effect on IL‐17 production. Antibody staining showed KCa3.1 channels in healthy colon and strong up‐regulation in association with infiltrating immune cells after induction of colitis. Despite poor plasma exposure, NS6180 (3 and 10 mg·kg−1b.i.d.) dampened colon inflammation and improved body weight gain as effectively as the standard IBD drug sulfasalazine (300 mg·kg−1q.d.).Conclusions and ImplicationsNS6180 represents a novel class of KCa3.1 channel inhibitors which inhibited experimental colitis, suggesting KCa3.1 channels as targets for pharmacological control of intestinal inflammation.