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 S. Slusher, Rana Rais

Research output: Contribution to journalArticlepeer-review

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 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.

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs'. Together they form a unique fingerprint.

Cite this