Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors
Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors
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DOI：
10.1073/pnas.97.2.925
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发表时间：
2000-01-18
影响因子：
11.1
通讯作者：
Marnett, LJ
中科院分区：
文献类型：
--
作者：
Kalgutkar, AS;Crews, BC;Marnett, LJ
所有非甾体类抗炎药（NSAIDs）均对环氧合酶（考克斯）同工酶有不同程度的抑制作用，这是其抗炎、镇痛和胃肠道副作用的原因。我们利用两种考克斯酶之间的生物化学差异来确定将含羧酸盐的NSAID转化为选择性考克斯-2抑制剂的策略。中等选择性考克斯-1抑制剂，如5，8，11，14-二十碳四炔酸（ETYA）和芳基乙酸和芬那酸NSAID，分别以吲哚美辛和甲氧那酸为例，羧酸酯部分的衍生化产生了有效的和选择性的考克斯-2抑制剂。在吲哚美辛系列中，酯和伯酰胺和仲酰胺作为选择性抑制剂上级叔酰胺。仅ETYA和甲氨酰胺酸的酰胺衍生物抑制考克斯-2;酯无活性或无选择性。抑制动力学表明，吲哚美辛酰胺表现为缓慢的，紧密结合的考克斯-2抑制剂和选择性是一个功能的时间依赖性步骤。鼠考克斯-2的定点突变表明，选择性的分子基础不同于母体NSAID和二芳基杂环化合物。选择性产生于底物结合位点的开口和顶点处的新型相互作用。本研究中的先导化合物是培养的炎症细胞中考克斯-2活性的有效抑制剂。此外，吲哚美辛酰胺在急性炎症的体内模型中是口服活性的、非溃疡性的抗炎剂。这种方法的扩展可以设想用于将所有含羧酸的NSAID修饰成选择性考克斯-2抑制剂。
All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.