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.
|
| 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.
|
|---|---|
| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 16 Pg. 7186-7198 (08 24 2017) ISSN: 1520-4804 [Electronic] United States |
| PMID | 28759224 (Publication Type: Journal Article) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!