A series of lumiracoxib derivatives were designed to explore the influence of isosteric substitution on balancing COX-2 inhibition and thromboxane A2 prostanoid (TP) receptor antagonism. The compounds were synthesized through a copper-catalyzed coupling procedure and characterized for their pKa values. TP receptor antagonism was assessed on human platelets; COX-2 inhibition was determined on human isolated monocytes and human whole blood. TPa receptor binding of the most promising compounds was evaluated through radioligand binding assays. Some of the isosteric substitutions at the carboxylic acid group afforded compounds with improved TP receptor antagonism; of these, a tetrazole derivative retained good COX-2 inhibitory activity and selectivity. The identification of this tetrazole acting as a balanced dual-acting compound in human whole blood, along with SAR analysis of the synthesized lumiracoxib derivatives, might contribute to the rational design of a new class of cardioprotective anti-inflammatory agents.

Designing Multitarget Anti-inflammatory Agents: Chemical Modulation of the Lumiracoxib Structure toward Dual Thromboxane Antagonists-COX-2 Inhibitors.

BERTINARIA, Massimo;CENA, Clara;ROLANDO, Barbara;LAZZARATO, Loretta;FRUTTERO, Roberta;GASCO, Alberto;
2012

Abstract

A series of lumiracoxib derivatives were designed to explore the influence of isosteric substitution on balancing COX-2 inhibition and thromboxane A2 prostanoid (TP) receptor antagonism. The compounds were synthesized through a copper-catalyzed coupling procedure and characterized for their pKa values. TP receptor antagonism was assessed on human platelets; COX-2 inhibition was determined on human isolated monocytes and human whole blood. TPa receptor binding of the most promising compounds was evaluated through radioligand binding assays. Some of the isosteric substitutions at the carboxylic acid group afforded compounds with improved TP receptor antagonism; of these, a tetrazole derivative retained good COX-2 inhibitory activity and selectivity. The identification of this tetrazole acting as a balanced dual-acting compound in human whole blood, along with SAR analysis of the synthesized lumiracoxib derivatives, might contribute to the rational design of a new class of cardioprotective anti-inflammatory agents.
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http://onlinelibrary.wiley.com
Massimo Bertinaria; Mohammed Abrar Abdul Gaffar Shaikh; Carola Buccellati; Clara Cena; Barbara Rolando; Loretta Lazzarato; Roberta Fruttero; Alberto Gasco; Malvina Hoxha; Valrie Capra; Angelo Sala; G. Enrico Rovati
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/120407
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