- New fluoro derivatives of the pyrazolo[5,1- c ][1,2,4]benzotriazine 5-oxide system: Evaluation of fluorine binding properties in the benzodiazepine site on γ-aminobutyrric acid type A (GABAA) receptor. design, synthesis, biological, and molecul
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In the search for potent ligands at the benzodiazepine site on the GABAA receptor, new fluoro derivatives of the pyrazolo[5,1-c][1,2,4] benzotriazine system were synthesized to evaluate the importance of the introduction of a fluorine atom in t
- Guerrini, Gabriella,Ciciani, Giovanna,Bruni, Fabrizio,Selleri, Silvia,Guarino, Chiara,Melani, Fabrizio,Montali, Marina,Daniele, Simona,Martini, Claudia,Ghelardini, Carla,Norcini, Monica,Ciattini, Samuele,Costanzo, Annarella
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experimental part
p. 7532 - 7548
(2011/02/21)
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- A new class of inhibitors of secretory phospholipase A2: enolized 1,3-dioxane-4,6-dione-5-carboxamides
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Enolized 1,3-dioxane-4,6-dione-5-carboxamides a were identified as a new class of inhibitors of secretory phospholipase A2 from human polymorphonuclear leucocytes (h-PMN PLA2).Among the more than 30 compounds synthesized, the most potent inhibitors (IC50 0.6-10 μM) were found in the series of 2,4-disubstituted phenyl analogues of a.Compound 1a was selected for evaluation of its biological profile.This substance potently inhibited secretory PLA2s from several sources other than human PMNs, with a clear preference for group II over group I PLA2, whereas humancytosolic PLA2 and phospholipase C were not significantly affected.Inhibition of h-PMN PLA2 was calcium-dependent.In intact mammalian cells stimulated in vitro, the release of arachidonic acid and the generation of prostaglandins and leukotrienes were inhibited at concentrations compatible with inhibition of PLA2 as an underlying mechanism.In animal models in vivo (carragheenan oedema, adjuvant arthritis, pertussis pleurisy) 1a showed antiinflammatory activity, although the effect was rather weak compared with standard reference compounds. secretory human PMN phospholipase A2 / enolized 1,3-dioxane-4,6-dione-5-carboxamide inhibitors / cellular eicosanoid synthesis / in vivo antiinflammatory activity / molecular modelling / structure-activity relationship
- Breitenstein, W.,Maerki, F.,Roggo, S.,Wiesenberg, I,Pfeilschifter, J.,et al.
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p. 649 - 658
(2007/10/02)
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