Fu Liqiang, Jiang Zhiteng, Cai Zhan, Liu Xin, He Huili, Yang Yushe
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 20103, China.
Bioorg Med Chem Lett. 2009 Sep 15;19(18):5407-10. doi: 10.1016/j.bmcl.2009.07.115. Epub 2009 Jul 28.
A phosphate prodrug strategy was investigated to address the problem of poor aqueous solubility of pleuromutilin analogues. Water-soluble phosphate prodrugs 6a, 6b and 6c of pleuromutilin analogues were designed and synthesized. Three compounds all exhibited excellent aqueous solubility (>50mg/mL) at near-neutral pH and sufficient stability in buffer solution. In particular, the phenol pleuromutilin prodrug 6c displayed favourable pharmacokinetic profiles and comparable potency with vancomycin against MSSA and MRSA strains in vivo.
为了解决截短侧耳素类似物水溶性差的问题，研究了一种磷酸酯前药策略。设计并合成了截短侧耳素类似物的水溶性磷酸酯前药6a、6b和6c。这三种化合物在近中性pH值下均表现出优异的水溶性（>50mg/mL），并在缓冲溶液中具有足够的稳定性。特别是，酚类截短侧耳素前药6c在体内对MSSA和MRSA菌株显示出良好的药代动力学特征，且效力与万古霉素相当。
