Ranatunge Ramani R, Augustyniak Michael E, Dhawan Vijay, Ellis James L, Garvey David S, Janero David R, Letts L Gordon, Richardson Stewart K, Shumway Mathew J, Trocha A Mark, Young Delano V, Zemtseva Irina S
NitroMed, Inc., 125 Spring St., Lexington, MA 02421, USA.
Bioorg Med Chem. 2006 Apr 15;14(8):2589-99. doi: 10.1016/j.bmc.2005.11.040. Epub 2005 Dec 13.
A series of glycolamide naproxen prodrugs containing a nitrate group as a nitric oxide (NO) donor moiety has been synthesized. These compounds were evaluated for their anti-inflammatory activity, naproxen release, and gastric tolerance. Compounds 4a, 4b, 5a, 5b, 7b, and 7c exhibited anti-inflammatory activity equivalent to that of the parent NSAID, naproxen-Na, in the rat carrageenan paw edema model. At equimolar doses relative to naproxen-Na, the NO-donor glycolamide derivatives 4a, 4b, 5a, 5b, 7b, and 7c were gastro-sparing in the rat. Naproxen formation from these NO-donor glycolamides varied among the structures examined, with the N-substituent on the amide group having a particular influence, and demonstrated their prodrug nature. Compound 7b was selected for exemplary demonstration that the glycolamide nitrates can be bioactivated to release NO. These data open the possibility that naproxen glycolamide nitrates may represent a safer alternative to naproxen as anti-inflammatory medicines.
已经合成了一系列含有硝酸根作为一氧化氮（NO）供体部分的甘醇酰胺萘普生前药。对这些化合物的抗炎活性、萘普生释放情况和胃耐受性进行了评估。在大鼠角叉菜胶足跖肿胀模型中，化合物4a、4b、5a、5b、7b和7c表现出与母体非甾体抗炎药萘普生钠相当的抗炎活性。相对于萘普生钠的等摩尔剂量下，NO供体甘醇酰胺衍生物4a、4b、5a、5b、7b和7c在大鼠中具有胃保护作用。在所研究的结构中，这些NO供体甘醇酰胺生成萘普生的情况各不相同，酰胺基团上的N-取代基有特别的影响，这证明了它们的前药性质。选择化合物7b作为示例，证明甘醇酰胺硝酸盐可以被生物活化以释放NO。这些数据表明，萘普生甘醇酰胺硝酸盐作为抗炎药物可能是比萘普生更安全的替代品。
