title: Designing multitarget anti-inflammatory agents: chemical modulation of the lumiracoxib structure toward dual thromboxane antagonists-COX-2 inhibitors.
abstract: A series of lumiracoxib derivatives were designed to explore the influence of isosteric substitution on balancing COX-2 inhibition and thromboxane A(2)  prostanoid (TP) receptor antagonism. The compounds were synthesized through a copper-catalyzed coupling procedure and characterized for their pK(a)  values. TP receptor antagonism was assessed on human platelets; COX-2 inhibition was determined on human isolated monocytes and human whole blood. TPα 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.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
authors.forename: Mohammed Abrar Abdul Gaffar
authors.initials: MA
authors.lastname: Shaikh
authors.forename: Carola
authors.initials: C
authors.lastname: Buccellati
authors.forename: Clara
authors.initials: C
authors.lastname: Cena
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
authors.forename: Malvina
authors.initials: M
authors.lastname: Hoxha
authors.forename: Valérie
authors.initials: V
authors.lastname: Capra
authors.forename: Angelo
authors.initials: A
authors.lastname: Sala
authors.forename: G Enrico
authors.initials: GE
authors.lastname: Rovati
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013777:Tetrazoles; D013931:Thromboxanes; D004008:Diclofenac; D051546:Cyclooxygenase 2; C473384:lumiracoxib