Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
Institute of Experimental Medicine of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic.
Eur J Med Chem. 2018 Aug 5;156:295-301. doi: 10.1016/j.ejmech.2018.07.010. Epub 2018 Jul 6.
As a part of a broader structure-activity relationship study of substituted 2-aminopyrimidines, the influence of the C-5 substitution on inhibition of prostaglandin E (PGE) production was studied. Thirty compounds were prepared starting from the corresponding 2-amino-4,6-dichloropyrimidines using Suzuki cross-coupling. It was shown previously that 2-amino-4,6-dichloropyrimidines with smaller C-5 substituent (hydrogen and methyl) were devoid of significant activity, while 5-butyl derivatives exhibited prominent potency. In this study, on the other hand, both monoaryl- and bisarylpyrimidines were potent inhibitors of PGE production regardless the length of the C-5 substituent (hydrogen, methyl, n-butyl). Moreover, the shorter the C-5 substituent the higher potency to inhibit PGE production was observed. 2-Amino-4,6-diphenylpyrimidine was the best inhibitor of PGE production with IC = 3 nM and no cytotoxicity. The most potent inhibitors deserve further preclinical evaluation as potential anti-inflammatory agents.
作为对取代的 2-氨基嘧啶结构-活性关系的更广泛研究的一部分，研究了 C-5 取代对抑制前列腺素 E（PGE）产生的影响。从相应的 2-氨基-4,6-二氯嘧啶开始，使用 Suzuki 交叉偶联合成了 30 种化合物。先前已经表明，具有较小 C-5 取代基（氢和甲基）的 2-氨基-4,6-二氯嘧啶没有明显的活性，而 5-丁基衍生物则表现出显著的效力。在这项研究中，另一方面，无论 C-5 取代基（氢、甲基、正丁基）的长度如何，单芳基和双芳基嘧啶都是 PGE 产生的有效抑制剂。此外，观察到 C-5 取代基越短，抑制 PGE 产生的效力越高。2-氨基-4,6-二苯基嘧啶是 PGE 产生的最佳抑制剂，IC = 3 nM，无细胞毒性。最有效的抑制剂值得进一步进行临床前评估，作为潜在的抗炎剂。
