Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells
Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells
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选择性环氧合酶 2 抑制剂 HN-56249 的药理学：一种新型化合物，在完整细胞中对人类酶表现出明显的偏好
DOI：
10.1007/s002109900192
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
D. Stimmeder
中科院分区：
文献类型：
--
作者：
J. Berg;H. Fellier;T. Christoph;P. Kremminger;M. Hartmann;H. Blaschke;F. Rovensky;R. Towart;D. Stimmeder
抽象的。 HN-56249 (3-(2,4-二氯噻吩氧基)-4-甲磺酰氨基苯磺酰胺)是一种高选择性环氧合酶(COX)-2抑制剂，是包含双环芳醚磺酰胺的新型COX抑制剂系列的原型；该系列中的 HN-56249 是最有效和最具选择性的人类 COX-2 抑制剂。HN-56249 仅适度抑制血小板聚集（作为 COX-1 活性的衡量标准）（IC50 26.5±1.7 µM）。在 LPS 刺激的单核细胞中，作为 COX-2 测量指标的前列腺素 (PG) F1α 的释放受到显着抑制（IC50 0.027±0.001 µM）。因此，HN-56249 在完整细胞中对 COX-2 的选择性约为 1000 倍。在全血测定中，HN-56249 仅显示出对 COX-2 的有效抑制活性（IC50 0.78±0.37 µM）。 COX-1 仅受到微弱抑制 (IC50 867±181 µM)。因此，HN-56249 对全血 COX-2 表现出超过 1000 倍的选择性。在完整细胞测定中，HN-56249 的 COX-2 选择性分别超过 COX-2 选择性抑制剂 3-环己氧基-4-甲基磺酰氨基-硝基苯 (NS-398) 和 6-(2,4-二氟苯氧基)-5-甲基磺酰氨基-1-茚满酮（氟舒脲）的八倍和三倍，在全血测定中约超过40倍。以下静脉注射给药 HN-56249 仅中度抑制角叉菜胶诱导的大鼠爪水肿（ID50 26.2±5.7 mg/kg，平均值±SEM），比吲哚美辛（ID50 2.1±0.2 mg/kg，平均值±SEM）效力低约十倍。口服 HN-56249 后，在角叉菜胶诱导的大鼠爪水肿试验中逆转热痛觉过敏，但效果比双氯芬酸低 30 倍。比较 HN-56249 在完整细胞中对人 COX-2 的抑制效力与对鼠 COX-2 的抑制效力，发现对人酶的选择性高出 300 倍。其他 COX-2 选择性芳醚磺酰胺也观察到类似的效果。相比之下，非 COX-2 选择性芳醚磺酰胺（包括高选择性 COX-1 抑制剂）对人类和小鼠 COX-2 的抑制作用大致相同。 总之，HN-56249 是一种新型有效且高选择性的 COX-2 抑制剂，在体外对人 COX-2 酶具有明显的偏好。尽管 HN-56249 具有出色的生物利用度和较长的血浆半衰期，但在啮齿动物中的抗炎作用仅为中等。我们认为观察到的这些不同的体外-体内效应可能是由于 COX-1 显着的炎症性前列腺素合成，或人类和啮齿动物 COX-2 之间的遗传差异，或两者兼而有之。
Abstract. HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesulfonamide), a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel series of COX inhibitors comprising bicyclic arylethersulfonamides; of this series HN-56249 is the most potent and selective human COX-2 inhibitor.HN-56249 inhibited platelet aggregation as a measure of COX-1 activity only moderately (IC50 26.5±1.7 µM). In LPS-stimulated monocytic cells the release of prostaglandin (PG) F1α as a measure of COX-2 was markedly inhibited (IC50 0.027±0.001 µM). Thus, HN-56249 showed an approximately 1000-fold selectivity for COX-2 in intact cells. In whole blood assays HN-56249 showed a potent inhibitory activity for COX-2 (IC50 0.78±0.37 µM) only. COX-1 was only weakly inhibited (IC50 867±181 µM). Hence, HN-56249 exhibited a greater than 1000-fold selectivity for whole blood COX-2. HN-56249 surpassed the COX-2 selectivities of the COX-2 selective inhibitors 3-cyclohexyloxy-4-methylsulfonylamino-nitrobenzene (NS-398) and 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and threefold, respectively, and in the whole blood assays by approximately 40-fold.Following i.v. administration HN-56249 inhibited carrageenan-induced rat paw oedema only moderately (ID50 26.2±5.7 mg/kg, mean ± SEM), approximately tenfold less potent than indomethacin (ID50 2.1±0.2 mg/kg, mean ± SEM). After oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan-induced rat paw oedema test, however, some 30-fold less potently than diclofenac. Comparing the inhibitory potency of HN-56249 against human COX-2 with that against murine COX-2 in intact cells revealed a 300-fold selectivity for the human enzyme. Similar effects were observed with other COX-2-selective arylethersulfonamides. In contrast, non-COX-2-selective arylethersulfonamides, including a highly selective COX-1 inhibitor, inhibited human and murine COX-2 approximately equipotently.In conclusion, HN-56249 is a novel potent and highly selective COX-2 inhibitor with a marked preference for the human COX-2 enzyme in vitro. Despite excellent bioavailability and the long plasma half-life of HN-56249, anti-inflammatory effects in rodents were only moderate. We suggest these differing in vitro-in vivo effects observed could be due to significant inflammatory prostaglandin synthesis by COX-1, or to the genetic differences between human and rodent COX-2, or to both.
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DOI：
10.1016/0929-7855(95)00015-i
发表时间：
1995-10-01
期刊：
JOURNAL OF LIPID MEDIATORS AND CELL SIGNALLING
影响因子：
--
作者：
OTTO, JC;SMITH, WL
通讯作者：
SMITH, WL
DOI：
10.1016/s0021-9258(18)98774-0
发表时间：
1991-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
D. Kujubu;B. Fletcher;B. Varnum;R. Lim;H. Herschman
通讯作者：
D. Kujubu;B. Fletcher;B. Varnum;R. Lim;H. Herschman
前列腺素内过氧化物合酶-1和-2在内质网中的定位。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Otto,JC;Smith,WL
通讯作者：
Smith,WL
影响因子：
15.9
作者：
SANO, H;HLA, T;WILDER, RL
通讯作者：
WILDER, RL
DOI：
10.1073/pnas.89.11.4888
发表时间：
1992-06-01
影响因子：
11.1
作者：
OBANION, MK;WINN, VD;YOUNG, DA
通讯作者：
YOUNG, DA