Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase

作者：Meng, Hu; Liu, Ying^*; Zhai, Yujing; Lai, Luhua

来源：European Journal of Medicinal Chemistry, 2013, 59: 160-167.

DOI：10.1016/j.ejmech.2012.10.057

• 5-Hydroxytryptamine
• Optimization
• PLA(2)
• LTA(4)H
• Dual function inhibitor

Dual function inhibitors targeting phospholipase A(2) (PLA(2)) and leukotriene A(4) hydrolase (LTA(4)H) may balance the arachidonic acid (AA) metabolic network and be used as new anti-inflammatory drugs. In previous study, we discovered multi-target drugs towards the AA metabolic network, among which a dual-target inhibitor (JMC08-4) for human nonpancreatic secretory phospholipase A(2) (hnps-PLA(2)) and human leukotriene A(4) hydrolase (LTA(4)H-h) was found. Based on the structure of compound JMC08-4, new dual-target inhibitors were designed assisted by molecular docking. In this report, a series of 5-hydroxytryptamine compounds were synthesized; and most of these title compounds showed more potent inhibitory activity than compound JMC08-4 in the in vitro bioassay against these two enzymes. The best one inhibited hnps-PLA(2) and LTA(4)H-h with IC50 values of 9.2 +/- 0.5 mu M and 2.4 +/- 1.4 mu M, respectively.

• 出版日期2013-1
• 单位北京大学