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

European Journal of Medicinal Chemistry
2013.0

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.

Knowledge Graph

Similar Paper

Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase
European Journal of Medicinal Chemistry 2013.0
Identification of a Potent, Selective, and Orally Active Leukotriene A<sub>4</sub> Hydrolase Inhibitor with Anti-Inflammatory Activity
Journal of Medicinal Chemistry 2008.0
Differential effects of a series of hydroxamic acid derivatives on 5-lipoxygenase and cyclooxygenase from neutrophils and 12-lipoxygenase from platelets and their in vivo effects on inflammation and anaphylaxis
Journal of Medicinal Chemistry 1989.0
Novel Dual Inhibitors of 5-Lipoxygenase and Thromboxane A2 Synthetase: Synthesis and Structure-Activity Relationships of 3-Pyridylmethyl-Substituted 2-Amino-6-hydroxybenzothiazole Derivatives
Journal of Medicinal Chemistry 1994.0
Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A<sub>4</sub> (LTA<sub>4</sub>) Hydrolase
Journal of Medicinal Chemistry 2000.0
Synthesis and Structure–Activity Relationship Studies of Novel Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase
Journal of Medicinal Chemistry 2013.0
5-Lipoxygenase inhibition by N-hydroxycarbamates in dual-function compounds
Bioorganic &amp; Medicinal Chemistry Letters 2005.0
Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization
Journal of Medicinal Chemistry 2022.0
(±)-trans-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a Potent Dual 5-Lipoxygenase Inhibitor and Platelet-Activating Factor Receptor Antagonist
Journal of Medicinal Chemistry 1998.0
4-Hydroxythiazole inhibitors of 5-lipoxygenase
Journal of Medicinal Chemistry 1991.0