Yang Michael G, Xiao Zili, Dhar T G Murali, Xiao Hai-Yun, Gilmore John L, Marcoux David, Xie Jenny H, McIntyre Kim W, Taylor Tracy L, Borowski Virna, Heimrich Elizabeth, Li Yu-Wen, Feng Jianlin, Fernandes Alda, Yang Zheng, Balimane Praveen, Marino Anthony M, Cornelius Georgia, Warrack Bethanne M, Mathur Arvind, Wu Dauh-Rurng, Li Peng, Gupta Anuradha, Pragalathan Bala, Shen Ding Ren, Cvijic Mary Ellen, Lehman-McKeeman Lois D, Salter-Cid Luisa, Barrish Joel C, Carter Percy H, Dyckman Alaric J
Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
J Med Chem. 2016 Dec 22;59(24):11138-11147. doi: 10.1021/acs.jmedchem.6b01433. Epub 2016 Dec 7.
We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.
我们描述了一种高效合成4a（BMS-986104）的路线。该合成中的关键步骤是三取代烯烃6的不对称硼氢化反应。特别是考虑到这类转化（6→7）中已知的困难，当前的方法提供了一种制备这类化合物的有效途径。此外，我们还揭示了4a在小鼠实验性自身免疫性脑脊髓炎（EAE）模型中的疗效，其与4c（芬戈莫德）相当。从机制上讲，在三维脑细胞培养试验中，4a对溶血磷脂酰胆碱（LPC）诱导的脱髓鞘表现出优异的髓鞘再生作用。
