Structure-based design of multi-target drugs using the example of dual inhibitors of LTA4 hydrolase and soluble epoxide hydrolase

以LTA4水解酶和可溶性环氧化物水解酶双抑制剂为例进行多靶点药物的结构设计

• 批准号: 225171069
• 负责人: Professor Dr. Eugen Proschak
• 金额: --
• 依托单位: Institut für Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225171069?language=en
• 关键词: Structure; based; design; multi; target

Inflammation is a pathophysiological state controlled by multiple pathways. One of the central regulators of inflammatory processes is the arachidonic acid cascade, which controls the onset and the active resolution of inflammation. Dual or multi-target inhibitors of enzymes involved in the arachidonic acid cascade have several advantages compared with selective compounds, including improved efficacy and more simple pharmacokinetic and pharmacodynamic properties than a combination of several drugs. Unfortunately, the rational design of polypharmacological compounds is a rather hard task and not well established. In the first three years we developed a strategy for the identification of starting points for rational multi-target drug discovery discovering novel inhibitors of 5-lipoxygenase and soluble epoxide hydrolase. Based on these results, the aim of the proposed project is the rational optimization of multi-target leads, which will be applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase. We assume that dual inhibition of both enzymes will lead to resolution of chronic inflammatory conditions by accumulation of anti-inflammatory lipid mediators.

炎症是一种由多种途径控制的病理生理状态。炎症过程的一个中心调节因子是花生四烯酸级联反应，它控制炎症的发作和主动消退。与选择性化合物相比，参与花生四烯酸级联反应的酶的双靶点或多靶点抑制剂具有几个优点，包括改善的功效和比几种药物的组合更简单的药代动力学和药效学性质。不幸的是，多药理学化合物的合理设计是一项相当艰巨的任务，并且没有很好地建立。在最初的三年里，我们开发了一种策略，用于确定合理的多靶点药物发现的起点，发现5-脂氧合酶和可溶性环氧化物水解酶的新型抑制剂。在此基础上，对多靶点先导化合物进行合理优化，并将其应用于可溶性环氧化物水解酶和白三烯A4水解酶的双抑制剂的设计。我们认为，这两种酶的双重抑制将导致通过抗炎脂质介质的积累来解决慢性炎症状况。

项目成果

Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ

• DOI: 10.3389/fphar.2019.00263
• 发表时间: 2019-03-20
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Goebel, Tamara;Diehl, Olaf;Kahnt, Astrid S.
• 通讯作者: Kahnt, Astrid S.

Computer-Aided Selective Optimization of Side Activities of Talinolol.

他林洛尔副活性的计算机辅助选择性优化

• DOI: 10.1021/acsmedchemlett.9b00075
• 发表时间: 2019
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Hiesinger;Kramer;Achenbach;Wittmann;Morisseau;Angioni;Geisslinger;Kaiser;Proschak;Steinhilber;Pogoryelov;Wagner;Hammock;Proschak
• 通讯作者: Proschak