Young Delano V, Cochran Edward D, Dhawan Vijay, Earl Richard A, Ellis James L, Garvey David S, Janero David R, Khanapure Subhash P, Letts L Gordon, Melim Terry L, Murty Madhavi G, Shumway Matthew J, Wey Shiow-Jyi, Zemtseva Irina S, Selig William M
Departments of Biology, 125 Spring St., Lexington, MA 02421, USA.
Biochem Pharmacol. 2005 Nov 1;70(9):1343-51. doi: 10.1016/j.bcp.2005.08.004.
Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n-butyl nitrate), for their ability to inhibit COX-1 and -2, deliver bioavailable nitric oxide, and release naproxen, using in vitro biochemical and pharmacological methods. In human whole blood, both CINODs showed inhibition, comparable to naproxen, of both COX isozymes and slowly released naproxen. Both CINODs donated bioavailable NO, as detected by cGMP induction in the pig kidney transformed cell line, LLC-PK1, but NMI-1182 was more potent by 30-100 times than AZD3582, GTN, GDN, and ISDN and considerably faster in inducing cGMP synthesis than AZD3582. The nitrate groups of GTN, NMI-1182, and AZD3582 appeared to be bioactivated via a common pathway, since each compound desensitized LLC-PK1 cells to subsequent challenge with the other compounds. Similar cGMP induction also occurred in normal, untransformed cells (human renal proximal tubule epithelial cells and hepatocytes from man, rat, and monkey); again, NMI-1182 was superior to AZD3582. NMI-1182 was also the more metabolically labile compound, releasing more absolute nitrate and nitrite (total NO(x)) in human stomach (in which NO is salutary) and liver S9 homogenates. Naproxen was also more rapidly freed from NMI-1182 than AZD3582 in human stomach, although liver S9 hydrolyzed both CINODs with similar rates. These in vitro tests revealed that NMI-1182 may be a better CINOD than AZD3582 because of its superior NO donating and naproxen liberating properties.
环氧化酶（COX，EC 1.14.99.1）抑制剂 - 一氧化氮（NO）供体（CINOD）杂合化合物是NSAID和昔布类药物治疗的一种有吸引力的替代方案。本报告使用体外生化和药理学方法，比较了两种CINOD，即NMI - 1182（萘普生 - 甘油二硝酸酯）和AZD3582（萘普生 - 正丁基硝酸酯）抑制COX - 1和 - 2、释放生物可利用的一氧化氮以及释放萘普生的能力。在人全血中，两种CINOD均显示出与萘普生相当的对两种COX同工酶的抑制作用，并缓慢释放萘普生。两种CINOD均能提供生物可利用的NO，如在猪肾转化细胞系LLC - PK1中通过cGMP诱导检测到的那样，但NMI - 1182的效力比AZD3582、GTN、GDN和ISDN强30 - 100倍，并且在诱导cGMP合成方面比AZD3582快得多。GTN、NMI - 1182和AZD3582的硝酸酯基团似乎通过共同途径进行生物活化，因为每种化合物都会使LLC - PK1细胞对随后用其他化合物进行的刺激产生脱敏作用。在正常的未转化细胞（人肾近端小管上皮细胞以及来自人、大鼠和猴子的肝细胞）中也发生了类似的cGMP诱导；同样，NMI - 1182优于AZD3582。NMI - 1182也是代谢更不稳定的化合物，在人胃（其中NO有益）和肝脏S9匀浆中释放更多的绝对硝酸盐和亚硝酸盐（总NO(x)）。在人胃中萘普生也比AZD3582更快地从NMI - 1182中释放出来，尽管肝脏S水解两种CINOD的速率相似。这些体外试验表明，由于其优越的NO供体和萘普生释放特性，NMI - 1182可能是比AZD3582更好的CINOD。
