Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Mitterweg 24, A-6020 Innsbruck, Austria.
Bioorg Chem. 2023 Oct;139:106685. doi: 10.1016/j.bioorg.2023.106685. Epub 2023 Jun 28.
Inflammatory responses are orchestrated by a plethora of lipid mediators, and perturbations of their biosynthesis or degradation hinder resolution and lead to uncontrolled inflammation, which contributes to diverse pathologies. Small molecules that induce a switch from pro-inflammatory to anti-inflammatory lipid mediators are considered valuable for the treatment of chronic inflammatory diseases. Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) are afflicted with side effects caused by the inhibition of beneficial prostanoid formation and redirection of arachidonic acid (AA) into alternative pathways. Multi-target inhibitors like diflapolin, the first dual inhibitor of soluble epoxide hydrolase (sEH) and 5-lipoxygenase-activating protein (FLAP), promise improved efficacy and safety but are confronted by poor solubility and bioavailability. Four series of derivatives bearing isomeric thiazolopyridines as bioisosteric replacement of the benzothiazole core and two series additionally containing mono- or diaza-isosteres of the phenylene spacer were designed and synthesized to improve solubility. The combination of thiazolo[5,4-b]pyridine, a pyridinylen spacer and a 3,5-Cl-substituted terminal phenyl ring (46a) enhances solubility and FLAP antagonism, while preserving sEH inhibition. Moreover, the thiazolo[4,5-c]pyridine derivative 41b, although being a less potent sEH/FLAP inhibitor, additionally decreases thromboxane production in activated human peripheral blood mononuclear cells. We conclude that the introduction of nitrogen, depending on the position, not only enhances solubility and FLAP antagonism (46a), but also represents a valid strategy to expand the scope of application towards inhibition of thromboxane biosynthesis.
炎症反应是由大量的脂质介质协调的，其生物合成或降解的扰动会阻碍其解决，并导致不受控制的炎症，从而导致多种病理。诱导从促炎到抗炎脂质介质转变的小分子被认为对治疗慢性炎症性疾病有价值。常用的非甾体抗炎药（NSAIDs）受到抑制有益的前列腺素形成和将花生四烯酸（AA）重定向到替代途径引起的副作用的困扰。多靶点抑制剂，如双功能环氧合酶/脂氧合酶抑制剂 diflapolin，是可溶性环氧化物水解酶（sEH）和 5-脂氧合酶激活蛋白（FLAP）的第一个双重抑制剂，有望提高疗效和安全性，但面临溶解度和生物利用度差的问题。设计并合成了四个系列的衍生物，这些衍生物以噻唑并[5,4-b]吡啶作为苯并噻唑核心的生物等排体，并另外包含一个或两个苯并二氮杂环戊烯的单或双等排体，以提高溶解度。噻唑并[5,4-b]吡啶、吡啶亚基和 3,5-Cl 取代的末端苯基环（46a）的组合增强了溶解度和 FLAP 拮抗作用，同时保留了 sEH 抑制作用。此外，噻唑并[4,5-c]吡啶衍生物 41b 虽然是一种效力较弱的 sEH/FLAP 抑制剂，但还可以减少激活的人外周血单核细胞中环血栓素的产生。我们得出结论，氮的引入（取决于位置）不仅增强了溶解度和 FLAP 拮抗作用（46a），而且还代表了一种扩展应用范围以抑制血栓素生物合成的有效策略。
