tPurpose: Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atheroscle-rosis) that require effective management of chronic pain may take advantage from new non-steroidalanti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activityand reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with acardioprotective component involving antagonism of thromboxane A2prostanoid (TP) receptor.Methods: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib,to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties.Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in anheterologous expression system by measuring prevention of aggregation and Gq-dependent productionof intracellular inositol phosphate induced by the stable thromboxane A2(TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho-monocytessuspension, respectively. COX selectivity was determined from dose–response curves by calculating aratio (COX-2/COX-1) of IC50values.Results: The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more activeantagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivityshowed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20was somehow less potent and selective for COX-2.Conclusion: These results indicate that compounds 18 and 20 are two novel combined TP receptor antag-onists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptorantagonism and that they may represent a first optimization of the original structure to improve theirmultitarget activity.

In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition

GARELLA, Davide;CENA, Clara;ROLANDO, Barbara;FRUTTERO, Roberta;BERTINARIA, Massimo
2016

Abstract

tPurpose: Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atheroscle-rosis) that require effective management of chronic pain may take advantage from new non-steroidalanti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activityand reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with acardioprotective component involving antagonism of thromboxane A2prostanoid (TP) receptor.Methods: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib,to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties.Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in anheterologous expression system by measuring prevention of aggregation and Gq-dependent productionof intracellular inositol phosphate induced by the stable thromboxane A2(TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho-monocytessuspension, respectively. COX selectivity was determined from dose–response curves by calculating aratio (COX-2/COX-1) of IC50values.Results: The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more activeantagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivityshowed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20was somehow less potent and selective for COX-2.Conclusion: These results indicate that compounds 18 and 20 are two novel combined TP receptor antag-onists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptorantagonism and that they may represent a first optimization of the original structure to improve theirmultitarget activity.
PHARMACOLOGICAL RESEARCH
103
132
143
http://www.sciencedirect.com/science/article/pii/S1043661815301390
Coxib; Cyclooxygenase; Inflammation; Multitarget drugs; NSAID; Thromboxane
Malvina Hoxha; Buccellati, Carola; Capra, Valérie; Garella, Davide; Cena, Clara; Rolando, Barbara; Fruttero, Roberta; Carnevali, Silvia; Sala, Angelo; Rovati, G.Enrico; Bertinaria, Massimo.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1551575
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