Landwehr Jens, George Sven, Karg Eva-Maria, Poeckel Daniel, Steinhilber Dieter, Troschuetz Reinhard, Werz Oliver
Department of Medicinal Chemistry, Institute for Pharmacy and Food Chemistry at the Emil-Fischer Center, Friedrich Alexander University Erlangen, Schuhstrasse 19, D-91052 Erlangen, Germany.
J Med Chem. 2006 Jul 13;49(14):4327-32. doi: 10.1021/jm050801i.
Compounds that inhibit 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of leukotrienes (LTs), possess potential for the treatment of inflammatory and allergic diseases as well as of atherosclerosis and cancer. Here we present the design and the synthesis of a series of novel 2-amino-5-hydroxyindoles that potently inhibit isolated human recombinant 5-LO as well as 5-LO in polymorphonuclear leukocytes, exemplified by ethyl 2-[(3-chlorophenyl)amino]-5-hydroxy-1H-indole-3-carboxylate (3n, IC(50) value congruent with 300 nM). Introduction of an aryl/arylethylamino group or 4-arylpiperazin-1-yl residues into position 2 of the 5-hydroxyindoles was essential for biological activity. Whereas the 4-arylpiperazin-1-yl derivatives were more potent in cell-free assays as compared to intact cell test systems, aryl/arylethylamino derivatives inhibited 5-LO activity in intact cells and cell-free assays almost equally well. On the basis of their 5-LO inhibitory properties, these novel 2-amino-5-hydroxyindoles represent potential candidates for the pharmacological intervention with LT-associated diseases.
抑制5-脂氧合酶（5-LO）（白三烯（LTs）生物合成中的关键酶）的化合物具有治疗炎症和过敏性疾病以及动脉粥样硬化和癌症的潜力。在此，我们展示了一系列新型2-氨基-5-羟基吲哚的设计与合成，这些化合物能有效抑制分离的人重组5-LO以及多形核白细胞中的5-LO，以2-[(3-氯苯基)氨基]-5-羟基-1H-吲哚-3-羧酸乙酯（3n，IC(50)值约为300 nM）为例。在5-羟基吲哚的2位引入芳基/芳基乙基氨基或4-芳基哌嗪-1-基残基对生物活性至关重要。与完整细胞测试系统相比，4-芳基哌嗪-1-基衍生物在无细胞测定中更有效，而芳基/芳基乙基氨基衍生物在完整细胞和无细胞测定中对5-LO活性的抑制效果几乎相同。基于它们对5-LO的抑制特性，这些新型2-氨基-5-羟基吲哚代表了对与LT相关疾病进行药理干预的潜在候选物。
