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首页> 外文期刊>RSC Advances >A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules
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A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules

机译：一种新型的三嗪-芳基-双吲哚衍生物同时抑制磷酸二酯酶IV和细胞粘附分子的表达

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Asthma, likemany inflammation related disorders, has a complex etiology. Drugs targeting multiple pathways may prove more efficacious in these complex disorders. Cyclic 30,50-adenosine monophosphate (cAMP) phosphodiesterase IV (PDE IV) is one of the validated targets in bronchial asthma and despite availability of some therapeutic molecules targeting PDE IV, molecules with better properties are desired. Eosinophileutrophil infiltration into lung may also be an important component of bronchial asthma in which increased expression of epithelial cell adhesion molecules may play an important role. This study describes the synthesis of a novel class of compounds 'triazine-aryl-bis-indoles' having a catechol derived structure constituting a part of 'triazine' and a part of 'bis-indole' moiety on it. This class of molecules potently inhibited both phosphodiesterase IV and expression of cell adhesion molecules ICAM-1 and VCAM-1. The best molecule of this class (compound 11) inhibited PDE IV activity in vitro, with an IC50 value of 14 mM compared to 12.7 mM for an existing drug rolipram. The compound 11 not only stabilized the cAMP level in human lung epithelial cells (L132) following stimulation with forskolin, but also inhibited TNF-alpha induced expression of cell adhesion molecules such as ICAM-1 and VCAM-1 in human umbilical vein epithelial cells (HUVECs). It also significantly inhibited the adhesion of human neutrophils to the endothelial monolayer (IC50 = 17.86 mM) in a dose dependent manner. Its absolute bioavailability (in mice) was found to be 70% and its toxicity and pharmacokinetic profiles are excellent. The dual activity of this class of molecules suggests that this class of molecules could have broad therapeutic applications in neutrophil dominant diseases such as severe asthma, COPD and acute lung injury.
机译：哮喘是许多与炎症相关的疾病，其病因复杂。在这些复杂的疾病中，靶向多种途径的药物可能更有效。环状30,50-腺苷单磷酸（cAMP）磷酸二酯酶IV（PDE IV）是支气管哮喘中经过验证的靶标之一，尽管有一些靶向PDE IV的治疗性分子可供使用，但仍需要具有更好性能的分子。嗜酸性粒细胞/嗜中性粒细胞向肺的浸润也可能是支气管哮喘的重要组成部分，其中上皮细胞粘附分子表达的增加可能起重要作用。这项研究描述了新颖的一类化合物“三嗪-芳基-双吲哚”的合成，该化合物具有邻苯二酚衍生的结构，该结构构成“三嗪”的一部分和“双吲哚”部分的一部分。这类分子有效抑制磷酸二酯酶IV和细胞粘附分子ICAM-1和VCAM-1的表达。此类中最好的分子（化合物11）在体外抑制PDE IV活性，IC50值为14 mM，而现有药物咯利普兰的IC50值为12.7 mM。化合物11不仅在福司可林刺激后稳定了人肺上皮细胞（L132）中的cAMP水平，而且还抑制了TNF-α诱导的人脐静脉上皮细胞中ICAM-1和VCAM-1等细胞粘附分子的表达（ HUVEC）。它还以剂量依赖性方式显着抑制人嗜中性粒细胞粘附于内皮单层（IC50 = 17.86 mM）。发现其绝对生物利用度（在小鼠中）为70％，并且其毒性和药代动力学特征都非常好。这类分子的双重活性表明，这类分子在中性粒细胞显性疾病（如严重的哮喘，COPD和急性肺损伤）中可能具有广泛的治疗应用。

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