Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 16, Pages 7186-7198Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00966
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Funding
- NCI NIH HHS [R01 CA193895] Funding Source: Medline
- NIDA NIH HHS [R01 DA037611] Funding Source: Medline
- NIMH NIH HHS [R25 MH080661, P01 MH105280, R01 MH104145, P30 MH075673] Funding Source: Medline
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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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