Nitrooxymethyl-substituted derivatives of Rofecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting activity in whole human blood, vasodilator potency on rat aorta strips, and for their capacity of inhibiting platelet aggregation of human platelet-rich plasma. The results show that their potency and selectivity in inhibiting COX isoforms, as well as their anti-aggregatory properties, are closely dependent on the position at which the NO-donor nitrooxymethyl function is introduced into the Rofecoxib scaffold. All the products were capable of dilating rat aorta strips precontracted with phenylephrine in a dose-dependent manner, through a cGMP-dependent mechanism. Compound 10 emerged as a quite potent COX-2-selective inhibitor endowed with good vasodilator activity. Interestingly, compound 19 behaved as a potent selective COX-1 inhibitor, and displayed good vasodilator and anti-aggregatory properties. The hydroxymethyl derivatives, potential metabolites of the nitrooxymethyl analogues, were similarly studied for a comparison.

Nitrooxymethyl-Substituted Analogues of Rofecoxib: Synthesis and Pharmacological Characterization

BOSCHI, Donatella;CENA, Clara;DI STILO, Antonella;ROLANDO, Barbara;FRUTTERO, Roberta;GASCO, Alberto
2010

Abstract

Nitrooxymethyl-substituted derivatives of Rofecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting activity in whole human blood, vasodilator potency on rat aorta strips, and for their capacity of inhibiting platelet aggregation of human platelet-rich plasma. The results show that their potency and selectivity in inhibiting COX isoforms, as well as their anti-aggregatory properties, are closely dependent on the position at which the NO-donor nitrooxymethyl function is introduced into the Rofecoxib scaffold. All the products were capable of dilating rat aorta strips precontracted with phenylephrine in a dose-dependent manner, through a cGMP-dependent mechanism. Compound 10 emerged as a quite potent COX-2-selective inhibitor endowed with good vasodilator activity. Interestingly, compound 19 behaved as a potent selective COX-1 inhibitor, and displayed good vasodilator and anti-aggregatory properties. The hydroxymethyl derivatives, potential metabolites of the nitrooxymethyl analogues, were similarly studied for a comparison.
CHEMISTRY & BIODIVERSITY
7
5
1173
1182
http://www3.interscience.wiley.com/journal/123450928/abstract
Rofecoxib; Inhibitors; Cyclooxygenase-inhibitory activity; NO Donors; Nitric oxide; Coxibs; Nitric-oxide release
Donatella Boschi; Clara Cena; Antonella Di Stilo; Barbara Rolando; Paola Manzini; Roberta Fruttero; Alberto Gasco
File in questo prodotto:
File Dimensione Formato  
reprint.pdf

accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 184.64 kB
Formato Adobe PDF
184.64 kB Adobe PDF Visualizza/Apri
rofecoxib aperto.pdf

accesso aperto

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 252.82 kB
Formato Adobe PDF
252.82 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/76135
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 14
social impact