1121795-67-2Relevant academic research and scientific papers
Discovery of 6-Diazo-5-oxo- l -norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma
Rais, Rana,Jan?a?ík, Andrej,Tenora, Luká?,Nedelcovych, Michael,Alt, Jesse,Englert, Judson,Rojas, Camilo,Le, Anne,Elgogary, Amira,Tan, Jessica,Monincová, Lenka,Pate, Kelly,Adams, Robert,Ferraris, Dana,Powell, Jonathan,Majer, Pavel,Slusher, Barbara S.
, p. 8621 - 8633 (2016)
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DON's therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DON's amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.
ADENOSINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
-
Paragraph 000199, (2021/02/05)
Disclosed here is an adenosine derivative prodrug that can have reverse transcriptase inhibitor activity in vivo. This disclosure is also directed to a pharmaceutical composition comprising the adenosine derivative that can be used for the treatment of HIV infection or RNA virus infection.
PRODRUGS OF GLUTAMINE ANALOGS
-
Page/Page column 90; 91, (2017/02/28)
Prodrugs of glutamine analogs, such as prodrugs of aza-serine, and 6-diazo-5-oxo-norleucine (DON), and 5-diazo-4-oxo-L-norvaline (L-DONV) are disclosed.
AMINO TRICYCLIC-NUCLEOSIDE COMPOUNDS, COMPOSITIONS, AND METHODS OF USE
-
Page/Page column 32-33, (2009/04/24)
Provided are compounds of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. The compounds and compositions are useful for treating viral infections caused by the Flaviviridae family of viruses.
