Nitrooxymethyl-Substituted Analogues of Rofecoxib: Synthesis and Pharmacological Characterization

被引：14

作者：

Boschi, Donatella ^{[1
]}

Cena, Clara ^{[1
]}

Di Stilo, Antonella ^{[1
]}

Rolando, Barbara ^{[1
]}

Manzini, Paola ^{[2
]}

Fruttero, Roberta ^{[1
]}

Gasco, Alberto ^{[1
]}

机构：

[1] Univ Turin, Dipartimento Sci & Tecnol Farmaco, I-10125 Turin, Italy

[2] AOU S Giovanni Battista, SIMT Banca del Sangue, I-10126 Turin, Italy

来源：

CHEMISTRY & BIODIVERSITY | 2010年 / 7卷 / 05期

关键词：

NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COX-2; INHIBITORS; CYCLOOXYGENASE INHIBITION; BIOLOGICAL EVALUATION; SELECTIVE INHIBITORS; OXIDE; RISK; 4-(4'-METHYLSULFONYLPHENYL)-3-PHENYL-2(5H)-FURANONE; CYCLO-OXYGENASE-2; AGENTS;

D O I：

10.1002/cbdv.200900421

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1173 / 1182

页数：10

共 33 条

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