TY - JOUR
T1 - N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs
AU - Zimmermann, Sarah C.
AU - Tichý, Tomáš
AU - Vávra, Jan
AU - Dash, Ranjeet P.
AU - Slusher, C. Ethan
AU - Gadiano, Alexandra J.
AU - Wu, Ying
AU - Jančařík, Andrej
AU - Tenora, Lukáš
AU - Monincová, Lenka
AU - Prchalová, Eva
AU - Riggins, Gregory J.
AU - Majer, Pavel
AU - Slusher, Barbara S.
AU - Rais, Rana
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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 0-t and a 1.7-fold improvement in brain AUC 0-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 AUC 0-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.
AB - 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 0-t and a 1.7-fold improvement in brain AUC 0-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 AUC 0-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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U2 - 10.1021/acs.jmedchem.7b01792
DO - 10.1021/acs.jmedchem.7b01792
M3 - Article
C2 - 29648826
AN - SCOPUS:85046839001
SN - 0022-2623
VL - 61
SP - 3918
EP - 3929
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 9
ER -