Miedzybrodzki Ryszard
Instytut Immunologii i Terapii Doświadczalnej PAN im. Ludwika Hirszfelda we Wrocławiu.
Postepy Hig Med Dosw (Online). 2004;58:438-48.
Since the synthesis of salicylic acid, research into the synthesis of new nonsteroidal anti-inflammatory drugs (NSAIDs) has continued in two directions: drugs with higher anti-inflammatory activity and those causing less adverse side-effects. Several very potent classic, non-selective NSAIDs were already available in the 1970's, but problems with their toxicity, especially gastro- and nephrotoxicity, have remained unsolved. The discovery of two cyclooxygenase (COX) isoforms, COX-1 and COX-2, was a breakthrough that led to obtaining the so-called coxibs, which selectively inhibit COX-2. This property makes this kind of NSAID less gastrotoxic than classic, non-selective NSAIDs. Other strategies to reduce the toxic effects of NSAIDs were their applications as prodrugs or purified enantiomers. The latest are the synthesis of classic NSAIDs combined with a chemical group that serves as a nitric oxide donor or the synthesis of double cyclooxygenase/5-lipoxygenase inhibitors. Simple inhibition of prostaglandin (PG) synthesis cannot completely stop the inflammatory process. Therefore new agents are tested for their influence on many other elements of the mechanism of inflammation, e.g. the formation of inflammatory cytokines, free radicals and biogenic amines by the stimulated inflammatory cells. Such pleiotropic activity of an NSAID might increase its anti-inflammatory action.NSAIDs are widely used not only for their anti-inflammatory, but also analgesic, antipyretic, and (as in case of aspirin) anti-coagulating activity. Results of the latest studies suggest that NSAIDs prevent colorectal cancer and may protect against the development of Alzheimer's disease as well. Precise studies of NSAIDs' mechanism of action (e.g. research on the genetic conditions of NSAID metabolism, the discovery of COX-3, studies on microsomal PGE synthase or PG receptors) will probably enable the synthesis of other more selectively acting compounds.
自水杨酸合成以来，新型非甾体抗炎药（NSAIDs）的合成研究一直朝着两个方向进行：具有更高抗炎活性的药物和副作用更少的药物。20世纪70年代就已经有几种非常有效的经典非选择性NSAIDs，但它们的毒性问题，尤其是胃肠道和肾毒性问题仍未得到解决。两种环氧化酶（COX）同工型COX-1和COX-2的发现是一个突破，由此获得了所谓的昔布类药物，它们选择性抑制COX-2。这种特性使得这类NSAIDs的胃肠道毒性比经典非选择性NSAIDs更低。降低NSAIDs毒性作用的其他策略包括将它们作为前体药物或纯化对映体使用。最新的方法是将经典NSAIDs与用作一氧化氮供体的化学基团结合进行合成，或者合成双环氧化酶/5-脂氧合酶抑制剂。单纯抑制前列腺素（PG）合成并不能完全阻止炎症过程。因此，人们测试新型药物对炎症机制中许多其他要素的影响，例如受刺激的炎症细胞产生炎性细胞因子、自由基和生物胺。NSAIDs的这种多效活性可能会增强其抗炎作用。NSAIDs不仅因其抗炎作用，还因其镇痛、解热以及（如阿司匹林）抗凝血活性而被广泛使用。最新研究结果表明，NSAIDs可预防结直肠癌，也可能预防阿尔茨海默病的发展。对NSAIDs作用机制的精确研究（例如对NSAIDs代谢的遗传条件的研究、COX-3的发现、微粒体PGE合酶或PG受体的研究）可能会促使合成其他更具选择性作用的化合物。
