Marceau F, Regoli D
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Québec, Canada.
Br J Pharmacol. 2008 Jul;154(6):1163-5. doi: 10.1038/bjp.2008.233. Epub 2008 Jun 9.
A surprising proportion of patients with inflammatory bowel disease (IBD) remain refractory to all classes of drugs presently in clinical use. Kinins are inflammatory mediators of potential relevance in IBD, because at least the kinin B1 receptor subtype is upregulated in human or animal intestinal inflammation and also both B1 and B2 receptors for kinins support inflammation and epithelial electrogenic ion transport that leads to secretory diarrhoea. In this issue of the BJP, Hara et al. report the therapeutic effect of a modern and selective nonpeptide kinin B1 receptor antagonist, SSR240612 ((2R)-2-(((3R)-3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulphonyl)amino)propanoyl)amino)-3-(4-((2R,6S)-2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide hydrochloride), with benefits such as decreased neutrophil influx and improved macroscopic tissue scoring. The results were corroborated using kinin B1 receptor gene-knockout mice. Further, kinin B1 receptor upregulation in this inflammatory model is partially dependent on TNF-alpha, a recognized target for IBD pharmacotherapy. More work is warranted to evaluate the value of the kinin B1 receptor antagonists as a novel anti-inflammatory therapeutic option for IBD.
相当大比例的炎症性肠病（IBD）患者对目前临床使用的所有药物类别均无反应。激肽是IBD中可能具有相关性的炎症介质，因为至少激肽B1受体亚型在人类或动物肠道炎症中上调，并且激肽的B1和B2受体均支持炎症以及导致分泌性腹泻的上皮电生性离子转运。在本期《英国药理学杂志》中，原田等人报道了一种现代选择性非肽类激肽B1受体拮抗剂SSR240612（(2R)-2-(((3R)-3-(1,3-苯并二氧杂环戊烯-5-基)-3-(((6-甲氧基-2-萘基)磺酰基)氨基)丙酰基)氨基)-3-(4-((2R,6S)-2,6-二甲基哌啶基)甲基)苯基)-N-异丙基-N-甲基丙酰胺盐酸盐）的治疗效果，其具有减少中性粒细胞流入和改善宏观组织评分等益处。使用激肽B1受体基因敲除小鼠证实了这些结果。此外，在该炎症模型中激肽B1受体的上调部分依赖于肿瘤坏死因子-α，这是IBD药物治疗的一个公认靶点。有必要开展更多工作来评估激肽B1受体拮抗剂作为IBD新型抗炎治疗选择的价值。
