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

Eur J Med Chem. 2013 Jan:59:160-7. doi: 10.1016/j.ejmech.2012.10.057. Epub 2012 Nov 17.

Abstract

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 IC(50) values of 9.2 ± 0.5 μM and 2.4 ± 1.4 μM, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Delivery Systems*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Phospholipase A2 Inhibitors*
  • Propionates / chemistry*
  • Propionates / pharmacology
  • Serotonin / chemistry*
  • Serotonin / pharmacology
  • Structure-Activity Relationship

Substances

  • 1,2-amino-3-(5-(benzyloxy)-1H-indol-3-yl)propanoic acid
  • Enzyme Inhibitors
  • Indoles
  • Phospholipase A2 Inhibitors
  • Propionates
  • Serotonin
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase