title: Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase.
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.
authors.affiliation: BNLMS, Center for Quantitative Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Meng
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhai
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D064801:Phospholipase A2 Inhibitors; D011422:Propionates / Q000737:chemistry* / Q000494:pharmacology; D012701:Serotonin / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C583880:1,2-amino-3-(5-(benzyloxy)-1H-indol-3-yl)propanoic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D064801:Phospholipase A2 Inhibitors; D011422:Propionates; D012701:Serotonin; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase