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.