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Inhibitors of microsomal prostaglandin E2 synthase-1 enzyme as emerging anti-inflammatory candidates.
Medicinal Research Reviews ( IF 10.9 ) Pub Date : 2014-01-13 , DOI: 10.1002/med.21306
Malkeet Singh Bahia 1 , Yogesh Kumar Katare 2 , Om Silakari 1 , Bhawna Vyas 3 , Pragati Silakari 4
Affiliation  

Cyclooxygenases (COX‐1 and COX‐2) catalyze the conversion of arachidonic acid (AA) into PGH2 that is further metabolized by terminal prostaglandin (PG) synthases into biologically active PGs, for example, prostaglandin E2 (PGE2), prostacyclin I2 (PGI2), thromboxane A2 (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 alpha (PGF). Among them, PGE2 is a widely distributed PG in the human body, and an important mediator of inflammatory processes. The successful modulation of this PG provides a beneficial strategy for the potential anti‐inflammatory therapy. For instance, nonsteroidal anti‐inflammatory agents (NSAIDs), both classical nonselective (cNSAIDs) and the selective COX‐2 inhibitors (coxibs) attenuate the generation of PGH2 from AA that in turn reduces the synthesis of PGE2 and modifies the inflammatory conditions. However, the long‐term use of these agents causes severe side effects due to the nonselective inhibition of other PGs, such as PGI2 and TXA2, etc. Microsomal prostaglandin E2 synthase‐1 (mPGES‐1), a downstream PG synthase, specifically catalyzes the biosynthesis of COX‐2‐derived PGE2 from PGH2, and describes itself as a valuable therapeutic target for the treatment of acute and chronic inflammatory disease conditions. Therefore, the small molecule inhibitors of mPGES‐1 would serve as a beneficial anti‐inflammatory therapy, with reduced side effects that are usually associated with the nonselective inhibition of PG biosynthesis.

中文翻译:

微粒体前列腺素E2合酶1酶的抑制剂可作为新兴的抗炎药物。

环氧合酶(COX-1和COX-2)催化花生四烯酸(AA)转化为PGH 2,再由末端前列腺素(PG)合成酶进一步代谢成具有生物活性的PG,例如前列腺素E 2(PGE 2),前列腺素I 2(PGI 2),血栓烷A 2(TXA 2),前列腺素D 2(PGD 2)和前列腺素F 2 alpha(PGF2α)。其中,PGE 2PG是人体中分布广泛的PG,是炎症过程的重要介质。这种PG的成功调节为潜在的抗炎治疗提供了有益的策略。例如,非甾体类抗炎药(NSAIDs),经典的非选择性(c NSAIDs)和选择性COX-2抑制剂(coxibs)都会削弱AA产生PGH 2的能力,进而降低PGE 2的合成并改变炎症条件。但是,由于对其他PG(例如PGI 2和TXA 2等)的非选择性抑制,长期使用这些药物会导致严重的副作用。微粒前列腺素E 2下游PG合酶synthase-1(mPGES-1)特异性催化PGH 2从COX-2衍生的PGE 2的生物合成,并将其描述为治疗急性和慢性炎症疾病的重要治疗靶标。因此,mPGES-1的小分子抑制剂可作为一种有益的抗炎治疗药物,其副作用通常与非选择性抑制PG生物合成有关,因此可减少副作用。
更新日期:2014-01-13
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