Qadri Fatimunnisa, Bader Michael
a Max-Delbrück Center for Molecular Medicine (MDC) , Berlin , Germany.
b Berlin Institute of Health (BIH) , Berlin , Germany.
Expert Opin Ther Targets. 2018 Jan;22(1):31-44. doi: 10.1080/14728222.2018.1409724. Epub 2017 Nov 30.
Kinins are peptide mediators exerting their pro-inflammatory actions by the selective stimulation of two distinct G-protein coupled receptors, termed BKB1R and BKB2R. While BKB2R is constitutively expressed in a multitude of tissues, BKB1R is hardly expressed at baseline but highly inducible by inflammatory mediators. In particular, BKB1R was shown to be involved in the pathogenesis of numerous inflammatory diseases. Areas covered: This review intends to evaluate the therapeutic potential of substances interacting with the BKB1R. To this purpose we summarize the published literature on animal studies with antagonists and knockout mice for this receptor. Expert Opinion: In most cases the pharmacological inhibition of BKB1R or its genetic deletion was beneficial for the outcome of the disease in animal models. Therefore, several companies have developed BKB1R antagonists and tested them in phase I and II clinical trials. However, none of the developed BKB1R antagonists was further developed for clinical use. We discuss possible reasons for this failure of translation of preclinical findings on BKB1R antagonists into the clinic.
激肽是一类肽类介质，通过选择性刺激两种不同的G蛋白偶联受体（分别称为BKB1R和BKB2R）发挥其促炎作用。虽然BKB2R在多种组织中组成性表达，但BKB1R在基线时几乎不表达，而是可被炎症介质高度诱导。特别是，已证明BKB1R参与多种炎症性疾病的发病机制。涵盖领域：本综述旨在评估与BKB1R相互作用的物质的治疗潜力。为此，我们总结了已发表的关于该受体拮抗剂和基因敲除小鼠的动物研究文献。专家观点：在大多数情况下，BKB1R的药理抑制或基因缺失对动物模型中的疾病结局有益。因此，几家公司已开发出BKB1R拮抗剂并在I期和II期临床试验中对其进行了测试。然而，所开发的BKB1R拮抗剂均未进一步开发用于临床。我们讨论了将BKB1R拮抗剂的临床前研究结果转化为临床应用失败的可能原因。
