10.1021/acs.jmedchem.7b01792.s002
Sarah
C. Zimmermann
Sarah
C.
Zimmermann
Tomáš Tichý
Tomáš
Tichý
Jan Vávra
Jan
Vávra
Ranjeet P. Dash
Ranjeet P.
Dash
C. Ethan Slusher
C. Ethan
Slusher
Alexandra J. Gadiano
Alexandra J.
Gadiano
Ying Wu
Ying
Wu
Andrej Jančařík
Andrej
Jančařík
Lukáš Tenora
Lukáš
Tenora
Lenka Monincová
Lenka
Monincová
Eva Prchalová
Eva
Prchalová
Gregory J. Riggins
Gregory
J. Riggins
Pavel Majer
Pavel
Majer
Barbara S. Slusher
Barbara S.
Slusher
Rana Rais
Rana
Rais
N‑Substituted
Prodrugs of Mebendazole Provide
Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs
American Chemical Society
2018
Compound 12
MBZ-C
MBZ-polymorph C
N-linked promoieties
bioavailable polymorph
plasma
AUC
broad-spectrum anthelmintic
bioavailability
solubility
Oral Bioavailability
Dogs Mebendazole
anticancer agent
physicochemical properties
prodrug approach
Aqueous Solubility
2018-04-12 00:00:00
Dataset
https://acs.figshare.com/articles/dataset/N_Substituted_Prodrugs_of_Mebendazole_Provide_Improved_Aqueous_Solubility_and_Oral_Bioavailability_in_Mice_and_Dogs/6163748
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 <b>12</b>, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl
promoiety, showed a >10 000-fold improvement in aqueous
solubility.
When evaluated in mice, <b>12</b> displayed a 2.2-fold higher
plasma AUC<sub>0–<i>t</i></sub> and a 1.7-fold improvement
in brain AUC<sub>0–<i>t</i></sub> with a calculated
oral bioavailability of 52%, as compared to 24% for MBZ-polymorph
C (MBZ-C), the most bioavailable polymorph. In dogs, <b>12</b> showed a 3.8-fold higher plasma AUC<sub>0–<i>t</i></sub> 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.