Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea.
Bioorg Med Chem Lett. 2013 Jan 1;23(1):75-80. doi: 10.1016/j.bmcl.2012.11.019. Epub 2012 Nov 15.
Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH(2) to PGE(2) and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC(50) of 1.1 μM) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10 μM concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors.
微粒体前列腺素 E 合酶-1（mPGES-1）是一种诱导型前列腺素 E 合酶，可催化前列腺素 PGH（2）转化为 PGE（2），是治疗炎症性疾病的新靶标。因此，鉴定具有新型骨架的 mPGES-1 抑制剂作为新型命中化合物或先导化合物，对于开发下一代抗炎药物至关重要。本文报道了磺酰胺基-1,2,3-三唑-4,5-二甲酸衍生物作为一种新型 mPGES-1 抑制剂的发现，该抑制剂是通过基于片段的虚拟筛选和实际化合物的体外抑制活性测定发现的。1-[2-（N- 苯磺酰胺基）乙基]-1H-1,2,3-三唑-4,5-二甲酸（6f）对人 mPGES-1 具有高选择性（约 1000 倍），IC50 为 1.1 μM，而对 COX-1 和 COX-2 的抑制作用较弱，在无细胞测定中。此外，在 10 μM 浓度下，在存在 0.1% Triton X-100 的情况下再次测试化合物 6f 的活性，发现其活性降低至原始活性的 1/4，而没有这种去污剂。与去污剂存在时的干扰抑制剂完全失活相比，因此，化合物 6f 可被视为 mPGES-1 的新型骨架部分干扰抑制剂，为设计更有效的 mPGES-1 抑制剂提供了优化方案。
