Effects of AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide], a novel inhibitor of human microsomal prostaglandin E synthase-1, on prostanoid biosynthesis in human monocytes in vitro
Effects of AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide], a novel inhibitor of human microsomal prostaglandin E synthase-1, on prostanoid biosynthesis in human monocytes in vitro
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DOI：
10.1016/j.bcp.2009.11.011
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发表时间：
2010-04-01
影响因子：
5.8
通讯作者：
Patrignani, Paola
中科院分区：
文献类型：
--
作者：
Bruno, Annalisa;Di Francesco, Luigia;Patrignani, Paola
微粒前列腺素(PG)E合成酶-1(mPGES-1)的抑制剂正在开发中，用于缓解疼痛。在mPGES-1基因敲除小鼠体内和体外发现的PGH(2)底物重定向到其他PG合成酶，可能会影响它们的有效性和安全性。我们通过研究新型mPGES-1抑制剂AF3442[N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluorometllyl)benzamide].在药物抑制下前列腺素E(2)、血栓素B-2、前列腺素F(2α)和6-酮-前列腺素F(1α)的合成以及环氧合酶同工酶和下游合酶的表达，来研究mPGES-1在脂多糖刺激的人单核细胞和全血中对PGH(2)代谢的作用。在脂多糖刺激的单核细胞中，AF3442对PGE(2)的合成呈浓度依赖性抑制，IC50为0.41mU。在1mU M时，AF3442对PGE(2)的选择性抑制作用最大，为61+/-3.3%(Mean+/-SEM，P<；0.01对DMSO载体)，而对其他前列腺素B_2、前列腺素F(2α)和6-酮-前列腺素F(1α)无明显影响。在脂多糖刺激的全血中，AF3442以浓度依赖的方式抑制PGE(2)的生物合成，IC50为29 mU M。10和100 mU M对mPGES-1活性的抑制有统计学意义(分别为38+/-14%，P<0.05和69+/-5%，P<0.01)。在100亩M以下，其他前列腺素类物质未受到明显影响。总之，AF3442是一种选择性的mPGES-1抑制剂，在血浆蛋白存在的情况下也能减少单核细胞PGE(2)的生成。对mPGES-1的药理抑制并不意味着将PGH(2)代谢转向单核细胞中的其他末端PG合成酶。这一观察结果的功能相关性值得在体内进行研究。(C)2009 Elsevier Inc.保留所有权利。
Inhibitors of microsomal prostaglandin (PG) E synthase-1 (mPGES-1) are being developed for the relief of pain. Redirection of the PGH(2) substrate to other PG synthases, found both in vitro and in vivo, in mPGES-1 knockout mice, may influence their efficacy and safety. We characterized the contribution of mPGES-1 to PGH(2) metabolism in lipopolysaccharide (LPS)-stimulated isolated human monocytes and whole blood by studying the synthesis of prostanoids [PGE(2), thromboxane (TX)B-2, PGF(2 alpha) and 6-keto-PGF(1 alpha)] and expression of cyclooxygenase (COX)-isozymes and down-stream synthases in the presence of pharmacological inhibition by the novel mPGES-1 inhibitor AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluorometllyl)benzamide]. AF3442 caused a concentration-dependent inhibition of PGE(2) in human recombinant rnPGES-1 with an IC50 of 0.06 mu M. In LPS-stimulated monocytes, AF3442 caused a concentration-dependent reduction of PGE(2) biosynthesis with an IC50 of 0.41 mu M. At 1 mu M, AF3442 caused maximal selective inhibitory effect of PGE(2) biosynthesis by 61 +/- 3.3% (mean +/- SEM, P < 0.01 versus DMSO vehicle) without significantly affecting other prostanoids (i.e. TXB2, PGF(2 alpha) and 6-keto-PGF(1 alpha)). In LPS-stimulated whole blood, AF3442 inhibited in a concentration-dependent fashion inducible PGE(2) biosynthesis with an IC50 of 29 mu M. A statistically significant inhibition of mPGES-1 activity was detected at 10 and 100 mu M (38 +/- 14%, P < 0.05, and 69 +/- 5%, P < 0.01, respectively). Up to 100 mu M, the other prostanoids were not significantly affected. In conclusion, AF3442 is a selective mPGES-1 inhibitor which reduced monocyte PGE(2) generation also in the presence of plasma proteins. Pharmacological inhibition of mPGES-1 did not translate into redirection of PGH(2) metabolism towards other terminal PG synthases in monocytes. The functional relevance of this observation deserves to be investigated in vivo. (C) 2009 Elsevier Inc. All rights reserved.