Regulation of phospholipase A2 enzymes: selective inhibitors and their pharmacological potential.
Regulation of phospholipase A2 enzymes: selective inhibitors and their pharmacological potential.
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DOI：
10.1016/s1054-3589(08)61011-x
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发表时间：
1995-01-01
期刊：
影响因子：
--
通讯作者：
Glaser, K B
中科院分区：
文献类型：
--
作者：
Glaser, K B
PLA 2研究领域在过去20年中发展迅速。对不同形式的PLA 2的动力学或影响动力学的因素有了更好的理解。正在发现新形式的PLA 2，如cPLA 2，其适合细胞内调节酶的作用。多种形式的PLA 2往往使阐明调节AA释放和随后的类花生酸产生的细胞机制复杂化。由于影响PLA 2动力学的因素和调节AA释放的PLA 2的未知性质（可能有一种以上），很难设计或分离特异性抑制剂。这篇综述讨论了选定的抑制剂类别，因为这些抑制剂在该领域产生了最激烈的研究。文献中报道了大量结构不同的化合物，据报道它们是体外PLA 2抑制剂，有些化合物具有抗炎活性（Wilkerson，1990; Connolly和罗宾逊，1993 a）。从文献的简要调查中可以清楚地看出，大部分PLA 2抑制剂具有局部抗炎活性。这可能是由于这些抑制剂的性质：因为它们是疏水性的，它们可能更容易被皮肤吸收，而口服时它们可能不会被吸收。根据数据，已在人体中对依那普利进行了临床评价，一种新的百时美施贵宝类retenoid衍生物可能进入银屑病临床试验（BMS-181162（XVI））;然而，市场上没有PLA 2抑制剂，临床开发也没有显著进展（表III）。这表明缺乏对这种酶的了解，以开发相关的抑制剂，这与缺乏对调节AA释放和类花生酸生物合成的相关PLA 2的了解有关。通过PLA 2抑制和降低AA可用性来调节类花生酸生物合成的概念仍然是治疗炎性疾病的可行治疗方法。由于PLA 2的复杂性质和细胞中PLA 2的多种形式，尚未获得该概念的证明。环氧合酶抑制剂的临床结果和5-脂氧合酶抑制剂的近期临床结果表明，如果抑制PLA 2导致两种脂质介质的减少，则应产生良好的抗炎化合物。PLA 2抑制剂的额外优势是降低PAF水平;然而，强效和特异性PAF拮抗剂的临床结果对降低PAF水平的潜在益处不太令人鼓舞。（400字处删节）
The area of PLA2 research has grown immensely over the past 20 years. There is a better understanding of the kinetics, or factors that affect the kinetics, of the different forms of PLA2. New forms of PLA2 are being discovered, such as the cPLA2, which fit the role of an intracellularly regulated enzyme. Multiple forms of PLA2 tend to complicate the elucidation of the cellular mechanisms that regulate AA release and the subsequent eicosanoid production. Because of the factors that affect PLA2 kinetics and the unknown nature of the PLA2 that regulates AA release (there may be more than one), it has been difficult to design or isolate specific inhibitors. This review discussed selected classes of inhibitors because these have generated the most intense research in the field. There is a multitude of structurally diverse compounds reported in the literature that have been reported to be inhibitors of PLA2 in vitro and some have been reported to have anti-inflammatory activity (Wilkerson, 1990; Connolly and Robinson, 1993a). It is clear from a brief survey of the literature that the bulk of PLA2 inhibitors have topical anti-inflammatory activity. This may be due to the nature of these inhibitors: because they are hydrophobic they may be more readily absorbed in the skin whereas when given orally they may not be absorbed. To data, manoalide has been clinically evaluated in man and a new Bristol-Myers Squibb retenoid derivative may enter clinical trials for psoriasis (BMS-181162 (XVI)); however, there are no PLA2 inhibitors on the market or significantly advanced in clinical development (Table III). This indicates the lack of understanding of this enzyme for the development of relevant inhibitors, which is related to the lack of understanding of the relevant PLA2 that regulates AA release and eicosanoid biosynthesis. The concept of regulation of eicosanoid biosynthesis by PLA2 inhibition and decreased AA availability still remains a viable therapeutic approach for the treatment of inflammatory diseases. The proof of this concept has not been obtained because of the complex nature of PLA2 and the multiple forms of PLA2 in the cell. Clinical results with cyclooxygenase inhibitors and recent clinical results with inhibitor of 5-lipoxygenase demonstrate that if inhibition of PLA2 results in reduction in both lipid mediators, a good anti-inflammatory compound should result. The added advantage of PLA2 inhibitors would be the reduction of PAF levels; however, the clinical results with potent and specific PAF antagonists has been less encouraging about the potential benefits of reduction in PAF levels.(ABSTRACT TRUNCATED AT 400 WORDS)