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

• Published in: Journal of medicinal chemistry Vol. 66; no. 22; pp. 15493 - 15510
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 23.11.2023; American Chemical Society
• Subjects: Acetamides - chemistry; Acetamides - pharmacology; Chemistry, Medicinal; Diazooxonorleucine - pharmacokinetics; Esters - therapeutic use; Glutamine; Humans; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Neoplasms - drug therapy; Pharmacology & Pharmacy; Prodrugs - chemistry; Prodrugs - pharmacology; Science & Technology; CLINICAL-PHARMACOLOGY; TRIAL; GLUTAMINE; CARBOXYLESTERASE; 6-DIAZO-5-OXO-L-NORLEUCINE DON; ANALOGS; GROWTH; AZASERINE; PHASE-I; BRAIN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• 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.