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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,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
- MeSH
- aminokapronáty aplikace a dávkování chemická syntéza farmakologie MeSH
- azosloučeniny aplikace a dávkování chemická syntéza farmakologie MeSH
- diazooxonorleucin aplikace a dávkování farmakologie MeSH
- glutaminasa antagonisté a inhibitory MeSH
- HIV infekce komplikace MeSH
- krev metabolismus MeSH
- kyselina glutamová metabolismus MeSH
- lidé MeSH
- mozek metabolismus MeSH
- myši inbrední C57BL MeSH
- neurokognitivní poruchy farmakoterapie etiologie MeSH
- nootropní látky aplikace a dávkování chemická syntéza farmakologie MeSH
- prasata MeSH
- prekurzory léčiv aplikace a dávkování chemická syntéza farmakologie MeSH
- stabilita léku MeSH
- virová nálož účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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
Citace poskytuje Crossref.org
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- $a 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.
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