Institute of Organic Chemistry and Biochemistry v.v.i , Czech Academy of Sciences , Prague 166 10 , Czech Republic.
J Med Chem. 2018 May 10;61(9):3918-3929. doi: 10.1021/acs.jmedchem.7b01792. Epub 2018 Apr 19.
Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC and a 1.7-fold improvement in brain AUC with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.
苯并咪唑（MBZ）最初被开发为一种广谱驱虫药，但最近已显示出作为抗癌药物的疗效。然而，由于其较差的水溶性导致生物利用度较差，MBZ 在癌症治疗中的应用具有挑战性。在此，我们开发了一种前药方法，使用各种 N-连接的促进剂，包括酰氧基甲基、氨甲酰氧基甲基和取代的膦氧甲基，以试图改善这些特性。含有 (((((异丙氧基羰基)氧基)甲氧基)膦酰基)氧基)甲基促进剂的化合物 12，在水中的溶解度提高了 >10000 倍。在小鼠中进行评估时，与最具生物利用度的多晶型物 MBZ 多晶型 C（MBZ-C）相比，12 显示出 2.2 倍的血浆 AUC 增加和 1.7 倍的脑 AUC 改善，计算的口服生物利用度为 52%。在狗中，与 MBZ-C 相比，12 显示出 3.8 倍的血浆 AUC 增加和 41%的口服生物利用度。总之，我们已经确定了一种具有更好理化性质和在小鼠和狗中增强生物利用度的 MBZ 前药。
