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Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-L-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery
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SYSNO ASEP 0578510 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-L-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery Tvůrce(i) Novotná, Kateřina (UOCHB-X) ORCID
Tenora, Lukáš (UOCHB-X) ORCID
Prchalová, E. (US)
Paule, J. (US)
Alt, J. (US)
Veeravalli, V. (US)
Lam, J. (US)
Wu, Y. (US)
Šnajdr, Ivan (UOCHB-X) ORCID
Gori, S. (US)
Mettu, V. S. (US)
Tsukamoto, T. (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. 66, č. 22 (2023), s. 15493-15510Poč.str. 18 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova phase-I ; 6-diazo-5-oxo-l-norleucine DON ; clinical pharmacology Obor OECD Organic chemistry CEP LTAUSA18166 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LX22NPO5102 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 001141575300001 EID SCOPUS 85178545949 DOI 10.1021/acs.jmedchem.3c01681 Anotace The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy, however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes. 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 2024 Elektronická adresa https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01681
Počet záznamů: 1