鉴定适用于局部应用的新型肿瘤坏死因子-α转换酶抑制剂。
Identification of novel TACE inhibitors compatible with topical application.
作者信息
Ouvry Gilles, Berton Yaël, Bhurruth-Alcor Yushma, Bonnary Laetitia, Bouix-Peter Claire, Bouquet Karine, Bourotte Marilyne, Chambon Sandrine, Comino Catherine, Deprez Benoît, Duvert Denis, Duvert Gwenaëlle, Hacini-Rachinel Feriel, Harris Craig S, Luzy Anne-Pascale, Mathieu Arnaud, Millois Corinne, Pascau Jonathan, Pinto Artur, Polge Gaëlle, Reitz Arnaud, Reversé Kevin, Rosignoli Carine, Taquet Nathalie, Hennequin Laurent F
机构信息
Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
Nestlé Skin Health R&D, Les Templiers 2400 Route des Colles, 06410 Biot, France.
出版信息
Bioorg Med Chem Lett. 2017 Apr 15;27(8):1848-1853. doi: 10.1016/j.bmcl.2017.02.035. Epub 2017 Feb 20.
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
用抗体靶向肿瘤坏死因子α信号通路已引发了银屑病治疗的一场革命。局部抑制肿瘤坏死因子α转换酶（TACE或ADAM17）可能会模拟这些效果，并有助于治疗轻至中度银屑病，且不会出现全身性TACE抑制剂所报道的副作用。本文介绍了寻找新型TACE抑制剂的研究工作。文中给出了酶促构效关系以及药物代谢动力学和物理化学数据。这项研究最终鉴定出了强效的酶抑制剂。结合先前发表的结果讨论了该系列化合物欠佳的细胞活性。
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