1,3-二芳基丙基-2- n-1-酮的合成及构效关系研究:环加氧酶和脂加氧酶的双重抑制剂。

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饶沛，陈QH, Knaus EE

1,3-二芳基丙基-2- n-1-酮的合成及构效关系研究:环加氧酶和脂加氧酶的双重抑制剂。

中华医学化学杂志，2006年3月9日;49(5):1668-83。

PubMed ID

16509583 (PubMed视图

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摘要

我们设计、合成了一组具有C-3 p-SO2Me COX-2药效团的1,3-二芳基丙基-2- yn1 -1-one(13,17,23,26和27)，并对其作为环氧合酶-1/2 (COX-1/2)和5/15-脂氧合酶(5/15-LOX)的潜在双重抑制剂进行了评估，这些抑制剂具有体内抗炎和镇痛活性。在这类化合物中，3-(4-甲基磺酰苯基)-1-(4-氟苯基)丙-2-yn-1- 1- 1 (13h)被确定为COX-2的有效选择性抑制剂(COX-2 IC50 = 0.1微米;SI = 300)，药效比rofecoxib强5倍(COX-2 IC50 = 0.5 microM;Si > 200)。在卡拉胶诱导的大鼠足水肿实验中，口服30 mg/kg剂量的卡拉胶3小时后，13小时显示出中等的抗炎活性(26%的炎症抑制)。相关双COX-1/2和5/15-LOX抑制剂3-(4-甲磺酰基)-1-(4-氰苯基)丙-2-yn-1- 1- 1 (13g, COX-1 IC50 = 31.5微米;COX-2 IC50 = 1.0 microM;Si = 31.5;5-LOX IC50 = 1.0 microM;15-LOX IC50 = 3.2 microM)表现出更强的抗炎活性(ED50 = 90 mg/kg)，优于参考药物阿司匹林(ED50 = 129 mg/kg)。 Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.

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绑定属性

药物	目标	财产	测量	pH值	温度(°C)
乙酰水杨酸	前列腺素G/H合成酶2	IC 50 (nM)	2400	8	37	细节
塞来昔布	前列腺素G/H合成酶2	IC 50 (nM)	70	8	37	细节
万	前列腺素G/H合成酶2	IC 50 (nM)	500	8	37	细节