Počet záznamů: 1
N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs
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SYSNO ASEP 0490659 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs Tvůrce(i) Zimmermann, S. C. (US)
Tichý, Tomáš (UOCHB-X) RID
Vávra, Jan (UOCHB-X) RID
Dash, R. P. (US)
Slusher, C. E. (US)
Gadiano, A. J. (US)
Wu, Y. (US)
Jančařík, Andrej (UOCHB-X) ORCID, RID
Tenora, Lukáš (UOCHB-X) ORCID
Monincová, Lenka (UOCHB-X)
Prchalová, E. (US)
Riggins, G. J. (US)
Majer, Pavel (UOCHB-X)
Slusher, B. S. (US)
Rais, R. (US)Zdroj.dok. Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 61, č. 9 (2018), s. 3918-3929Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova anthelmintic drug mebendazole ; water soluble prodrugs ; in vivo Vědní obor RIV CC - Organická chemie Obor OECD Organic chemistry Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000432204800011 EID SCOPUS 85046839001 DOI 10.1021/acs.jmedchem.7b01792 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2019
Počet záznamů: 1