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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00490659" target="_blank" >RIV/61388963:_____/18:00490659 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1021/acs.jmedchem.7b01792" target="_blank" >http://dx.doi.org/10.1021/acs.jmedchem.7b01792</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.7b01792" target="_blank" >10.1021/acs.jmedchem.7b01792</a>

Result language

angličtina

Original language name

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

Original language description

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 >10000-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, 12showed 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10401 - Organic chemistry

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

—

Volume of the periodical

61

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

12

Pages from-to

3918-3929

UT code for WoS article

000432204800011

EID of the result in the Scopus database

2-s2.0-85046839001