State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Jiangsu Nhwa Pharmaceutical Co., Ltd., 69 Democratic South Road, Xuzhou 221116, Jiangsu, China.
Molecules. 2018 Apr 24;23(5):996. doi: 10.3390/molecules23050996.
GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.
GLYX-13 是一种 NMDAR 甘氨酸部位部分激动剂，被发现是一种有前景的抗抑郁药，具有快速作用且无氯胺酮样副作用。然而，报道的合成工艺路线存在产率低和使用不友好试剂的缺点。在这里，我们报告了一种规模化合成 GLYX-13 的方法，在公斤级规模上采用无柱层析策略，总收率为 30%，对偶联和脱保护反应条件进行了系统优化。同时，通过 X 射线单晶衍射确定了 GLYX-13 的前体化合物的绝对构型。最后，通过全细胞膜片钳技术在小鼠皮层神经元中验证了 GLYX-13 的活性。
