| Autor: |
Novotná, Kateřina, Tenora, Lukáš, Prchalová, Eva, Paule, James, Alt, Jesse, Veeravalli, Vijay, Lam, Jenny, Wu, Ying, Šnajdr, Ivan, Gori, Sadakatali, Mettu, Vijaya Saradhi, Tsukamoto, Takashi, Majer, Pavel, Slusher, Barbara S., Rais, Rana |
| Zdroj: |
Journal of Medicinal Chemistry; November 2023, Vol. 66 Issue: 22 p15493-15510, 18p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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