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

Sarah C. Zimmermann, Tomáš Tichý, Jan Vávra, Ranjeet P. Dash, C. Ethan Slusher, Alexandra J. Gadiano, Ying Wu, Andrej Jančařík, Lukáš Tenora, Lenka Monincová, Eva Prchalová, Gregory J Riggins, Pavel Majer, Barbara Slusher, Rana Rais

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3918-3929
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number9
DOIs
StatePublished - May 10 2018

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Mebendazole
Prodrugs
Solubility
Biological Availability
Dogs
Anthelmintics
Antineoplastic Agents
Brain
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs. / Zimmermann, Sarah C.; Tichý, Tomáš; Vávra, Jan; Dash, Ranjeet P.; Slusher, C. Ethan; Gadiano, Alexandra J.; Wu, Ying; Jančařík, Andrej; Tenora, Lukáš; Monincová, Lenka; Prchalová, Eva; Riggins, Gregory J; Majer, Pavel; Slusher, Barbara; Rais, Rana.

In: Journal of Medicinal Chemistry, Vol. 61, No. 9, 10.05.2018, p. 3918-3929.

Research output: Contribution to journalArticle

Zimmermann, SC, Tichý, T, Vávra, J, Dash, RP, Slusher, CE, Gadiano, AJ, Wu, Y, Jančařík, A, Tenora, L, Monincová, L, Prchalová, E, Riggins, GJ, Majer, P, Slusher, B & Rais, R 2018, 'N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs', Journal of Medicinal Chemistry, vol. 61, no. 9, pp. 3918-3929. https://doi.org/10.1021/acs.jmedchem.7b01792
Zimmermann, Sarah C. ; Tichý, Tomáš ; Vávra, Jan ; Dash, Ranjeet P. ; Slusher, C. Ethan ; Gadiano, Alexandra J. ; Wu, Ying ; Jančařík, Andrej ; Tenora, Lukáš ; Monincová, Lenka ; Prchalová, Eva ; Riggins, Gregory J ; Majer, Pavel ; Slusher, Barbara ; Rais, Rana. / N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 9. pp. 3918-3929.
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AU - Dash, Ranjeet P.

AU - Slusher, C. Ethan

AU - Gadiano, Alexandra J.

AU - Wu, Ying

AU - Jančařík, Andrej

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AU - Monincová, Lenka

AU - Prchalová, Eva

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