1-（5-羧基吲哚-1-基）丙烷-2-酮作为人胞质磷脂酶A2α的抑制剂：生物电子等排体苯并咪唑、苯并三唑和吲唑类似物的合成与性质
1-(5-Carboxyindol-1-yl)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: synthesis and properties of bioisosteric benzimidazole, benzotriazole and indazole analogues.
作者信息
Bovens Stefanie, Kaptur Martina, Elfringhoff Alwine Schulze, Lehr Matthias
机构信息
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany.
出版信息
Bioorg Med Chem Lett. 2009 Apr 15;19(8):2107-11. doi: 10.1016/j.bmcl.2009.03.019. Epub 2009 Mar 10.
The indole ring systems of the cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2) and the isomeric 6-carboxylic acid (3) were replaced by benzimidazole, benzotriazole and indazole scaffolds, respectively. The effect of the structural variations on cPLA(2)alpha inhibitory potency, metabolic stability and solubility was studied. The lead 2 and the indazole-5-carboxylic acid 28 were the metabolically most stable compounds in an assay with rat liver microsomes, while the benzimidazole-5-carboxylic acid derivative 13 possessed the best water solubility (22 microg/mL at pH 7.4). The indazole-5-carboxylic acid 28 revealed the highest cPLA(2)alpha inhibitory potency of the compounds in this series. With an IC(50)-value of 0.005 microM it was about sevenfold more active than the lead 2.
胞质型磷脂酶A(2)α（cPLA(2)α）抑制剂1-[3-(4-辛基苯氧基)-2-氧代丙基]吲哚-5-羧酸（2）和异构体6-羧酸（3）的吲哚环系统分别被苯并咪唑、苯并三唑和吲唑支架取代。研究了结构变化对cPLA(2)α抑制效力、代谢稳定性和溶解度的影响。在大鼠肝微粒体试验中，先导化合物2和吲唑-5-羧酸28是代谢最稳定的化合物，而苯并咪唑-5-羧酸衍生物13具有最佳的水溶性（在pH 7.4时为22μg/mL）。吲唑-5-羧酸28在该系列化合物中显示出最高的cPLA(2)α抑制效力。其IC(50)值为0.005μM，活性比先导化合物2高约7倍。
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