- Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase
-
Dual function inhibitors targeting phospholipase A2 (PLA 2) and leukotriene A4 hydrolase (LTA4H) 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 A2 (hnps-PLA 2) and human leukotriene A4 hydrolase (LTA4H-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 LTA4H-h with IC50 values of 9.2 ± 0.5 μM and 2.4 ± 1.4 μM, respectively.
- Meng, Hu,Liu, Ying,Zhai, Yujing,Lai, Luhua
-
p. 160 - 167
(2013/03/13)
-
- Brain-specific drug delivery
-
The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: (a) compounds of the formula wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier, with the proviso that when [DHC] is STR1 wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH2 or OH function group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and (b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entitles [D--QC]+ X- are also disclosed.
- -
-
-
- Brain-specific drug delivery
-
The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: (a) compounds of the formula wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier, with the proviso that when [DHC] is STR1 wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH2 or OH functional group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and (b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entities [D-QC]+ Y- are also disclosed.
- -
-
-
- [9H]-Pyrido-[3,4-b]-indoles
-
Novel 1,2,3,4-tetrahydro-[9H-pyrido-[3,4-b]-indoles of the formula STR1 wherein R and R1 are individually selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy of 1 to 5 carbon atoms and benzyloxy with the proviso that R1 is not hydroxy when R is halogen, alkoxy or benzyloxy and their non-toxic, pharmaceutically acceptable acid addition salts having tranquillizing properties and their preparation.
- -
-
-