Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-L-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery

0578510 - ÚOCHB 2024 RIV US eng J - Článek v odborném periodiku
Novotná, Kateřina - Tenora, Lukáš - Prchalová, E. - Paule, J. - Alt, J. - Veeravalli, V. - Lam, J. - Wu, Y. - Šnajdr, Ivan - Gori, S. - Mettu, V. S. - Tsukamoto, T. - Majer, Pavel - Slusher, B. S. - Rais, R.
Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-L-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery.
Journal of Medicinal Chemistry. Roč. 66, č. 22 (2023), s. 15493-15510. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA MŠMT LTAUSA18166; GA MŠMT LX22NPO5102
Institucionální podpora: RVO:61388963
Klíčová slova: phase-I * 6-diazo-5-oxo-l-norleucine DON * clinical pharmacology
Obor OECD: Organic chemistry
Impakt faktor: 7.3, rok: 2022
Způsob publikování: Open access
https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01681

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.
Trvalý link: https://hdl.handle.net/11104/0347498