Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of pirinixic acid

Werz O; Greiner C; Koeberle A; Hoernig C; George S; Popescu L; Syha I; Schubert-Zsilavecz M; Steinhilber D

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Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of pirinixic acid

机译：基于吡rin酸结构的新型有效的5-脂氧合酶抑制剂

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A novel class of potent 5-lipoxygenase (5-LO) product synthesis inhibitors based on the structure of pirinixic acid (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, compound 1) is presented. Systematic profilin g, of 1, i.e., esterification of the carboxylic acid, cc-substitution, and replacement of the o-dimethylaniline by 6-aminoquinoline, leads to potent Suppressors of 5-LO product formation in activated polymorphonuclear leukocytes, exemplified by ethyl 2-[4-chloro-6-(quinoline-6-ylamino)-pyrimidin-2-ylsulfanyl]octane-1-carboxylate (6d, IC50 = 0.6 mu M). These derivatives may possess potential for intervention with inflammatory and allergic diseases.

机译：提出了一种新型的有效的5-脂氧合酶（5-LO）产物合成抑制剂，该抑制剂基于吡ix酸（4-氯-6-（2,3-二甲苯基）-2-嘧啶基硫代乙酸，化合物1）的结构。 1的系统性蛋白g，即羧酸的酯化，cc取代和6-氨基喹啉替代邻二甲基苯胺，可在活化的多形核白细胞中有效抑制5 -LO产物的形成，例如乙基2 -[4-氯-6-（喹啉-6-基氨基）-嘧啶-2-基硫烷基]辛烷-1-羧酸酯（6d，IC 50 ＝0.6μM）。这些衍生物可能具有干预炎症和过敏性疾病的潜力。

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《Journal of Medicinal Chemistry》 |2008年第17期|共5页
作者
Werz O; Greiner C; Koeberle A; Hoernig C; George S; Popescu L; Syha I; Schubert-Zsilavecz M; Steinhilber D;
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正文语种 eng
中图分类药学;
关键词
ENZYME-ACTIVITY; AGONISTS; PROTEIN; ALPHA; DERIVATIVES; ACTIVATION; STRESS;

机译：酶活性;促进剂;蛋白质;α;衍生物;活化;应力;

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专利

1. Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of pirinixic acid [J] . Werz O, Greiner C, Koeberle A, Journal of Medicinal Chemistry . 2008,第17期

机译：基于吡rin酸结构的新型有效的5-脂氧合酶抑制剂
2. Pirinixic Acid Derivatives as Novel Dual Inhibitors of Microsomal Prostaglandin E-2 Synthase-1 and 5-Lipoxygenase [J] . Koeberle A, Zettl H, Greiner C, Journal of Medicinal Chemistry . 2008,第24期

机译：Pirinixic酸衍生物作为微粒体前列腺素E-2合酶1和5-Lipoxygenase的新型双重抑制剂。
3. Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5-lipoxygenase inhibitor. [J] . Yatabe T, Kayakiri H, Kawai Y, Chemical and Pharmaceutical Bulletin . 1998,第10期

机译：5-脂氧合酶抑制剂的研究。二。 FR110302的发现，光学拆分和对映选择性合成，FR110302是一种高效的非氧化还原型5-脂氧合酶抑制剂。
4. Discovering Potent Inhibitors Against the β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) of Helicobacter pylori: Structure-Based Design, Synthesis, Bioassay, and Crystal Structure Determination [C] . Lingyan He, Hualiang Jiang, Hong Liu, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：发现针对幽门螺杆菌的β-羟酰基-酰基载体蛋白脱水酶（FabZ）的有效抑制剂：基于结构的设计，合成，生物测定和晶体结构确定
5. Part I: 1,3,4-oxadiazoles in tandem Diels-Alder, 1,3-dipolar cycloaddition reactions: A rapid synthesis of vinca alkaloid motifs. Part II: Exceptionally potent inhibitors of fatty acid amide hydrolase [D] . Wilkie, Gordon David 2002

机译：第一部分：串联Diels-Alder中的1,3,4-恶二唑，1,3-偶极环加成反应：长春花生物碱基序的快速合成。第二部分：脂肪酸酰胺水解酶的超强抑制剂
6. A pirinixic acid derivative (LP105) inhibits murine 5-lipoxygenase activity and attenuates vascular remodelling in a murine model of aortic aneurysm [O] . M Revermann, A Mieth, L Popescu, 2011

机译：吡rin酸衍生物（LP105）在鼠主动脉瘤模型中抑制鼠5-脂氧合酶的活性并减弱血管重塑
7. Tertiary Alkylamines as Nucleophiles in Substitution Reactions at Heteroaromatic Halide During the Synthesis of the Highly Potent Pirinixic Acid Derivative 2-(4-Chloro-6-(2,3dimethylphenylamino)pyrimidin-2-ylthio)octanoic Acid (YS-121) [O] . Matthias Gabler, Manfred Schubert-zsilavecz 2013

机译：叔烷基胺作为亲核试剂在高强环丙氨酸衍生物2-（4-氯-6-（2,3-二甲基苯基氨基）嘧啶-2-基硫基）辛酸（YS-121）合成过程中在杂芳族卤化物上的取代反应中

Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of pirinixic acid

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