Di Micco Simone, Terracciano Stefania, Cantone Vincenza, Fischer Katrin, Koeberle Andreas, Foglia Antonio, Riccio Raffaele, Werz Oliver, Bruno Ines, Bifulco Giuseppe
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
Eur J Med Chem. 2018 Jan 1;143:1419-1427. doi: 10.1016/j.ejmech.2017.10.039. Epub 2017 Oct 23.
mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE levels induced by inflammatory stimuli, with neither affecting PGE constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug-like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities.
微粒体前列腺素E合酶-1（mPGES-1）是一种依赖谷胱甘肽的膜蛋白，参与前列腺素E（PGE）生成的最后一步，并且已被公认为是开发抗炎和抗癌药物的一个关键靶点。业已证实，它能选择性地控制由炎症刺激诱导产生的PGE水平，既不影响组成性产生的PGE，也不影响内稳态前列腺素，因此与具有严重副作用的传统抗炎药物相比，对其进行调节可能是控制与PGE相关疾病的更好策略。尽管对鉴定有效的mPGES-1抑制剂作为有吸引力的药物开发候选物进行了深入研究，但除了最近进入临床试验的LY3023705之外，所披露的分子均无法用于临床，因此迫切需要发现具有更好类药性质的新型有效mPGES-1抑制剂。继续我们旨在鉴定能够与该酶相互作用的新化学平台的工作，在此我们描述了通过对一小批围绕两个主要片段合成可得的分子进行处理和对接，发现了具有基于1-氟-2,4-二硝基联苯支架的强效mPGES-1调节剂，这两个主要片段是在我们的计算机模拟筛选中披露的。已合成并测试了得分最高的命中化合物，其中五个预测化合物显示出能有效抑制mPGES-1酶，而不影响环氧化酶（COX）的活性。
