title: In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition.
abstract: OBJECTIVE
  Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (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 an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of 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-monocytes suspension, respectively. COX selectivity was determined from dose-response curves by calculating a ratio (COX-2/COX-1) of IC50 values.
  
  
  RESULTS
  The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more active antagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2 values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivity showed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20 was somehow less potent and selective for COX-2.
  
  
  CONCLUSIONS
  These results indicate that compounds 18 and 20 are two novel combined TP receptor antagonists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptor antagonism and that they may represent a first optimization of the original structure to improve their multitarget activity.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Malvina
authors.initials: M
authors.lastname: Hoxha
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Carola
authors.initials: C
authors.lastname: Buccellati
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, via di Rudinì 8, 20142 Milano, Italy.
authors.forename: Valérie
authors.initials: V
authors.lastname: Capra
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Ital.
authors.forename: Davide
authors.initials: D
authors.lastname: Garella
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Ital.
authors.forename: Clara
authors.initials: C
authors.lastname: Cena
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Ital.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Ital.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carnevali
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sala
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy. Electronic address: genrico.rovati@unimi.it.
authors.forename: G Enrico
authors.initials: GE
authors.lastname: Rovati
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Ital.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D009281:Naphthalenes; D011422:Propionates; D017482:Receptors, Thromboxane; D004008:Diclofenac; D009288:Naproxen; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C501362:terutroban; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C473384:lumiracoxib
keywords: Coxib; Cyclooxygenase; Inflammation; Multitarget drugs; NSAID; Thromboxane