生物利用度
前药
化学
甲苯咪唑
溶解度
药理学
口服
药代动力学
驱虫药
水溶液
生物化学
有机化学
医学
生态学
兽医学
生物
作者
Sarah C. Zimmermann,Tomáš Tichý,Jan Vávra,Ranjeet Prasad Dash,C. Ethan Slusher,Alexandra J. Gadiano,Ying Wu,Andrej Jančařík,Lukáš Tenora,Lenka Monincová,Eva Prchalová,Gregory J. Riggins,Pavel Majer,Barbara S. Slusher,Rana Rais
标识
DOI:10.1021/acs.jmedchem.7b01792
摘要
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 AUC0–t and a 1.7-fold improvement in brain AUC0–t 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 AUC0–t 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.
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