Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
Bioorg Med Chem. 2012 Sep 15;20(18):5483-95. doi: 10.1016/j.bmc.2012.07.042. Epub 2012 Aug 2.
P2Y(6) nucleotide receptor (P2Y(6)-R) plays important physiological roles, such as insulin secretion and reduction of intraocular pressure. However, this receptor is still lacking potent and selective agonists to be used as potential drugs. Here, we synthesized uracil nucleotides and dinucleotides, substituted at the C5 and/or P(α) position with methoxy and/or borano groups, 18-22. Compound 18A, R(p) isomer of 5-OMe-UDP(α-B), is the most potent and P2Y(6)-R selective agonist currently known (EC(50) 0.008 μM) being 19-fold more potent than UDP and showing no activity at uridine nucleotide receptors, P2Y(2)- and P2Y(4)-R. Analogue 18A was highly chemically stable under conditions mimicking gastric juice acidity (t(1/2) = 16.9 h). It was more stable to hydrolysis by nucleotide pyrophosphatases (NPP1,3) than UDP (15% and 28% hydrolysis by NPP1 and NPP3, respectively, vs 50% and 51% hydrolysis of UDP) and metabolically stable in blood serum (t(1/2) = 17 vs 2.4, 11.9, and 21 h for UDP, 5-OMe-UDP, and UDP(α-B), respectively). This newly discovered highly potent and physiologically stable P2Y(6)-R agonist may be of future therapeutic potential.
P2Y(6) 核苷酸受体 (P2Y(6)-R) 发挥着重要的生理作用，如胰岛素分泌和降低眼内压。然而，目前仍然缺乏强效且选择性的 P2Y(6)-R 激动剂作为潜在药物。在此，我们合成了尿嘧啶核苷酸和二核苷酸，在 C5 和/或 P(α)位取代了甲氧基和/或硼烷基团，得到了 18-22。化合物 18A，R(p)异构体 5-OMe-UDP(α-B)，是目前已知的最有效和选择性最强的 P2Y(6)-R 激动剂（EC(50) 为 0.008 μM），比 UDP 强 19 倍，对尿苷核苷酸受体、P2Y(2)-和 P2Y(4)-R 没有活性。类似物 18A 在模拟胃液酸度的条件下具有很高的化学稳定性（t(1/2) = 16.9 h）。它对核苷酸焦磷酸酶 (NPP1,3) 的水解比 UDP 更稳定（NPP1 和 NPP3 分别水解 15%和 28%，而 UDP 水解 50%和 51%），在血清中代谢稳定（t(1/2) = 17，而 UDP、5-OMe-UDP 和 UDP(α-B)的半衰期分别为 2.4、11.9 和 21 h）。这种新发现的强效且生理稳定的 P2Y(6)-R 激动剂可能具有未来的治疗潜力。
