Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

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

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00966

DOI: 10.1021/acs.jmedchem.7b00966

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