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N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders
MT. Nedelcovych, L. Tenora, BH. Kim, J. Kelschenbach, W. Chao, E. Hadas, A. Jančařík, E. Prchalová, SC. Zimmermann, RP. Dash, AJ. Gadiano, C. Garrett, G. Furtmüller, B. Oh, G. Brandacher, J. Alt, P. Majer, DJ. Volsky, R. Rais, BS. Slusher,
Language English Country United States
Document type Journal Article
- MeSH
- Aminocaproates administration & dosage chemical synthesis pharmacology MeSH
- Azo Compounds administration & dosage chemical synthesis pharmacology MeSH
- Diazooxonorleucine administration & dosage pharmacology MeSH
- Glutaminase antagonists & inhibitors MeSH
- HIV Infections complications MeSH
- Blood metabolism MeSH
- Glutamic Acid metabolism MeSH
- Humans MeSH
- Brain metabolism MeSH
- Mice, Inbred C57BL MeSH
- Neurocognitive Disorders drug therapy etiology MeSH
- Nootropic Agents administration & dosage chemical synthesis pharmacology MeSH
- Swine MeSH
- Prodrugs administration & dosage chemical synthesis pharmacology MeSH
- Drug Stability MeSH
- Viral Load drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
Department of Medicine Icahn School of Medicine at Mount Sinai New York New York 10029 United States
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