Seerden Jean-Paul G, Leusink-Ionescu Gabriela, Leguijt Robin, Saccavini Catherine, Gelens Edith, Dros Bas, Woudenberg-Vrenken Titia, Molema Grietje, Kamps Jan A A M, Kellogg Richard M
Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
Bioorg Med Chem Lett. 2014 Mar 1;24(5):1352-7. doi: 10.1016/j.bmcl.2014.01.034. Epub 2014 Jan 28.
The design, synthesis and biological evaluation of novel triazolyl p38α MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38α MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38α MAPK inhibitor 88 (IC50=0.096 μM) displayed the most promising in vitro activity.
本文描述了新型三唑基p38α丝裂原活化蛋白激酶（MAPK）抑制剂的设计、合成及生物学评价，这些抑制剂具有改善的水溶性，可用于靶向病变内皮细胞的阳离子脂质体（SAINT - O - Somes）制剂。通过功能性叠氮化物与2 - 炔基咪唑和等排恶唑的“点击”反应引入水溶性基团，以生成两个1,4 - 二取代1,2,3 - 三唑基p38α MAPK抑制剂的小型文库。筛选具有低IC50值和所需理化性质的三唑类化合物，用于体外下调促炎基因表达，并将其制成SAINT - O - Somes制剂。三唑基p38α MAPK抑制剂88（IC50 = 0.096 μM）表现出最有前景的体外活性。
