Karg Eva-Maria, Luderer Susann, Pergola Carlo, Bühring Ulrike, Rossi Antonietta, Northoff Hinnak, Sautebin Lidia, Troschütz Reinhard, Werz Oliver
Department of Chemistry and Pharmacy, Chair of Pharmaceutical Chemistry, Friedrich Alexander University Erlangen, Erlangen, Germany.
J Med Chem. 2009 Jun 11;52(11):3474-83. doi: 10.1021/jm900212y.
Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC(50) values of 0.23 and 0.086 microM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC(50) = 0.83-1.6 microM) and significantly prevented leukotriene B(4) production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics.
通过5-脂氧合酶（5-LO）抑制剂对白三烯生物合成进行药理抑制是干预炎症和过敏性疾病的一种策略。我们最近在基于细胞和无细胞试验中展示了2-氨基-5-羟基-1H-吲哚作为有效的5-LO抑制剂。结构优化产生了新型苯并[g]吲哚-3-羧酸盐，以2-（3-氯苄基）-5-羟基-1H-苯并[g]吲哚-3-羧酸乙酯（化合物11a）为例，其在人中性粒细胞和重组人5-LO中抑制5-LO活性，IC（50）值分别为0.23和0.086 microM。值得注意的是，11a在人全血试验中有效阻断5-LO产物形成（IC（50）=0.83-1.6 microM），并显著预防角叉菜胶处理大鼠胸腔渗出液中白三烯B（4）的产生，这与胸膜炎严重程度降低相关。总之，基于它们对5-LO的高效力和在生物系统中的显著疗效，这些新型且简单的苯并[g]吲哚-3-羧酸盐可能具有作为抗炎治疗药物的潜力。
