Stereoselective inhibition of inducible cyclooxygenase by chiral nonsteroidal antiinflammatory drugs
Stereoselective inhibition of inducible cyclooxygenase by chiral nonsteroidal antiinflammatory drugs
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DOI：
10.1002/j.1552-4604.1996.tb05040.x
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发表时间：
1996-06-01
影响因子：
2.9
通讯作者：
Mauleon, D
中科院分区：
文献类型：
--
作者：
Carabaza, A;Cabre, F;Mauleon, D
研究了手性非甾体抗炎药(NSAIDs)-酮洛芬、氟比洛芬和酮咯酸-对诱导型环氧化酶（COX-2）的立体选择性抑制作用。在三种不同的体外系统中评估了COX-2的活性和抑制作用：豚鼠全血、脂多糖（LPS）刺激的人单核细胞和羊胎盘纯化的COX-2制剂。结果与三种平行体外模型（凝血豚鼠血、人多形核白细胞和公羊精囊纯化COX-1）对组成型环氧合酶（COX-1）的抑制作用进行了比较。在全血模型中，两种同功酶均被s -对映体抑制，但s -酮洛芬对COX-2的抑制作用最强（IC50 = 0.024 mu mol/L）。3种r -对映体对同工酶的抑制作用均小于40%。r -对映体对COX的抑制作用可能归因于s -对映体的污染（约0.5%）。在完整细胞中也观察到COX-2抑制的显著程度的对映体选择性。s -对映体抑制单核细胞COX-2的IC50值为2 ~ 25 nmol/L，比相应的r -对映体强100 ~ 500倍。s -酮洛芬对羊胎盘中COX-2的抑制作用（IC50 = 5.3 μ mol/L）略低于s -酮酸（IC50 = 0.9 μ mol/L）和s -氟比洛芬（IC50 = 0.48 μ mol/L），而r -对映体基本无活性（IC50大于等于80 μ mol/L）。由此得出结论，本研究研究的手性非甾体抗炎药对COX-2和COX-1同工酶的抑制具有相当的立体选择性，并且先前观察到的外消旋非甾体抗炎药对COX-2的抑制几乎完全归因于它们的s -对映体。
The stereoselective inhibition of inducible cyclooxygenase (COX-2) by chiral nonsteroidal antiinflammatory drugs (NSAIDs)-ketoprofen, flurbiprofen, and ketorolac- has been investigated. The activity and inhibition of COX-2 was assessed in three different in vitro systems: guinea pig whole blood, lipopolysaccharide (LPS)-stimulated human monocytes, and purified preparations of COX-2 from sheep placenta. The results were compared with the inhibition of constitutive cyclooxygenase (COX-1) in three parallel in vitro models: clotting guinea pig blood, human polymorphonuclear leukocytes, and purified COX-1 from ram seminal vesicles. In the whole blood model, both isoenzymes were inhibited by S-enantiomers with equal potency but S-ketoprofen was the most active on COX-2 (IC50 = 0.024 mu mol/L). In contrast, both isoenzymes were inhibited less than 40% by all three R-enantiomers at high concentration (>1 mu mol/L). The inhibition of COX by the R-enantiomers may be attributed to contamination with the S-enantiomers (approximately 0.5%). A significant degree of enantioselectivity in COX-2 inhibition was also observed in intact cells. The S-enantiomers inhibited COX-2 from monocytes with IC50 values in the range of 2 to 25 nmol/L, being 100 to 500-fold more potent than the corresponding R-enantiomers. Finally, S-ketoprofen inhibited COX-2 from sheep placenta (IC50 = 5.3 mu mol/L) with slightly less potency than S-ketorolac (IC50 = 0.9 mu mol/L) and S-flurbiprofen (IC50 = 0.48 mu mol/L), whereas the R-enantiomers were found to be essentially inactive (IC50 2 greater than or equal to 80 mu mol/L). It is concluded that the chiral NSAIDs studied here inhibit with comparable stereoselectivity both COX-2 and COX-1 isoenzymes, and that the inhibition of COX-2 previously observed for racemic NSAIDs should be attributed almost exclusively to their S-enantiomers.