Nitrooxymethyl-Substituted Analogues of Rofecoxib: Synthesis and Pharmacological Characterization

✍ Scribed by Donatella Boschi; Clara Cena; Antonella Di Stilo; Barbara Rolando; Paola Manzini; Roberta Fruttero; Alberto Gasco

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 185 KB
• Volume: 7
• Category: Article
• ISSN: 1612-1872
• DOI: 10.1002/cbdv.200900421

✦ Synopsis

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.