N‑Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

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.

美贝唑（MBZ）作为一种广谱抗蠕虫药物而被开发，但近期却显示出作为抗癌药物的潜力。然而，由于其溶解性差，导致生物利用度低，使用MBZ治疗癌症存在挑战。鉴于此，本研究开发了一种前药策略，包括多种N-连接促溶剂，如酰氧甲基、氨基酰氧甲基和取代的膦酸氧甲基，旨在改善这些特性。化合物12，含有(((((异丙氧羰基)氧)甲基)膦酸基)氧)甲基促溶剂，其在水中的溶解性提高了超过10,000倍。在小鼠模型中评估时，12显示出2.2倍更高的血浆AUC0–t和1.7倍改善的大脑AUC0–t，与MBZ-聚合物C（MBZ-C）相比，MBZ-C的生物利用度最高，为24%，而12的口服生物利用度计算值为52%。在狗模型中，12显示出3.8倍更高的血浆AUC0–t，与MBZ-C的11%相比，其口服生物利用度为41%。总之，本研究已鉴定出一种MBZ的前药，其在小鼠和狗模型中均表现出更优的物理化学性质和增强的生物利用度。