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

Michael T. Nedelcovych, Lukáš Tenora, Boe Hyun Kim, Jennifer Kelschenbach, Wei Chao, Eran Hadas, Andrej Jančařík, Eva Prchalová, Sarah C. Zimmermann, Ranjeet P. Dash, Alexandra J. Gadiano, Caroline Garrett, Georg Furtmüller, Byoungchol Oh, Gerald Brandacher, Jesse Alt, Pavel Majer, David J. Volsky, Rana Rais, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7136-7198
Number of pages63
JournalJournal of medicinal chemistry
Volume60
Issue number16
DOIs
StatePublished - Aug 24 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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