Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
J Med Chem. 2010 Feb 25;53(4):1597-615. doi: 10.1021/jm901517k.
The injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of the Siglec family (sialic-acid binding immunoglobulin-like lectin). In earlier studies, we identified the lead structure 5, which shows a 250-fold improved in vitro affinity for MAG compared to the tetrasaccharide binding epitope of GQ1balpha (1), the best physiological MAG ligand described so far. By modifying the 2- and 5-position, the affinity of 5 could be further improved to the nanomolar range (-->19a). Docking studies to a homology model of MAG allowed the rationalization of the experimental binding properties. Finally, pharmacokinetic parameters (stability in the cerebrospinal fluid, logD and permeation through the BBB) indicate the drug-like properties of the high-affinity antagonist 19a.
由于特定的抑制剂，受伤的成年哺乳动物中枢神经系统对于轴突再生来说是一种抑制性环境，其中包括髓鞘相关糖蛋白 (MAG)，它是 Siglec 家族的成员（唾液酸结合免疫球蛋白样凝集素）。在早期的研究中，我们确定了先导结构 5，与迄今为止描述的最佳生理 MAG 配体 GQ1balpha（1）的四糖结合表位相比，5 在体外对 MAG 的亲和力提高了 250 倍。通过修饰 2-位和 5-位，5 的亲和力可以进一步提高到纳摩尔范围（-->19a）。对 MAG 同源模型的对接研究使实验结合特性合理化。最后，药代动力学参数（在脑脊液中的稳定性、logD 和通过 BBB 的渗透）表明高亲和力拮抗剂 19a 具有类药性。
