生物化学和药理tetrasubstituted furanone高度选择性cox - 2抑制剂。

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Riendeau D,珀西瓦尔博士博伊斯年代,Brideau C, Charleson年代,Cromlish W, Ethier D,埃文斯J, Falgueyret JP, Ford-Hutchinson啊,戈登R,格雷格G, Gresser M, Guay J, Kargman年代,莱热年代,曼奇尼JA,奥尼尔G, Ouellet M,罗杰信息战,Therien M,王Z,韦伯JK Wong E,成龙CC, et al。

生物化学和药理tetrasubstituted furanone高度选择性cox - 2抑制剂。

Br杂志。1997;121(1):105 - 17所示。

PubMed ID

9146894 (在PubMed

]

文摘

1。(5-dimethyl-3 DFU(5日)- 3-fluorophenyl 4 - (4-methylsulphonyl) phenyl-2 (5 h)呋喃)被认定为小说的口服和高度选择性cyclo-oxygenase-2 (cox - 2)抑制剂。2。考克斯在稳定转染CHO细胞与人类同功酶,DFU抑制花生四烯酸的acid-dependent生产前列腺素E2 (PGE2)至少1000倍选择性COX - 2 (IC50 = 41 + / - 14海里)在COX-1 (IC50 > 50 microM)。吲哚美辛是一个强有力的抑制剂的COX-1 (IC50 = 18 + / - 3 nM)和cox - 2 (IC50 = 26 + / - 6海里)在相同的试验条件下。大幅增加选择性的DFU消炎痛也观察到COX-1介导血栓素B2 (TXB2)生产Ca2 + ionophore-challenged人类血小板(IC50 > 50 microM和4.1 + / - 1.7 nM,分别)。3所示。DFU造成时间与Ki纯化重组人类抑制cox - 2,价值140 + / - 68 microM初始可逆结合酶和2 k值0.11 + / - 0.06 s - 1为一阶速率常数的形成一个紧密地绑定酶抑制剂复杂。可比的62 + / - 26 microM值和0.06 + / - 0.01 s - 1,分别得到吲哚美辛。酶抑制剂复合物被发现有一个1:1化学计量学和分离只有非常缓慢(t1/2 = 1 - 3 h)恢复完整的酶抑制剂和活跃。 The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodolac and SC-58125 were about 10 times more potent inhibitors of COX-1 than DFU. The order of potency of various inhibitors was diclofenac > indomethacin approximately naproxen > nimesulide approximately meloxicam approximately piroxicam > NS-398 approximately SC-57666 > SC-58125 > CGP 28238 approximately etodolac > L-745,337 > DFU. 7. DFU inhibited dose-dependently both the carrageenan-induced rat paw oedema (ED50 of 1.1 mg kg-1 vs 2.0 mg kg-1 for indomethacin) and hyperalgesia (ED50 of 0.95 mg kg-1 vs 1.5 mg kg-1 for indomethacin). The compound was also effective at reversing LPS-induced pyrexia in rats (ED50 = 0.76 mg kg-1 vs 1.1 mg kg-1 for indomethacin). 8. In a sensitive model in which 51Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg-1, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg-1), meloxicam (3 mg kg-1) or etodolac (10-30 mg kg-1). A 5 day administration of DFU in squirrel monkeys (100 mg kg-1) did not affect chromium leakage in contrast to diclofenac (1 mg kg-1) or naproxen (5 mg kg-1). 9. The results indicate that COX-1 inhibitory effects can be detected for all selective COX-2 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX-1, a consistent high selectivity of inhibition of COX-2 over COX-1 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss of integrity of the gastrointestinal tract at doses >200 fold higher than efficacious doses in models of inflammation, pyresis and hyperalgesia. These results provide further evidence that prostanoids derived from COX-1 activity are not important in acute inflammatory responses and that a high therapeutic index of anti-inflammatory effect to gastropathy can be achieved with a selective COX-2 inhibitor.

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药物靶点

药物	目标	类	生物	药理作用	行动
Etodolac	前列腺素合成酶1 G / H	蛋白质	人类	未知的	抑制剂	细节