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

• Published in: Journal of medicinal chemistry Vol. 60; no. 16; pp. 7186 - 7198
• Main Authors: Nedelcovych, Michael T, Tenora, Lukáš, Kim, Boe-Hyun, Kelschenbach, Jennifer, Chao, Wei, Hadas, Eran, Jančařík, Andrej, Prchalová, Eva, Zimmermann, Sarah C, Dash, Ranjeet P, Gadiano, Alexandra J, Garrett, Caroline, Furtmüller, Georg, Oh, Byoungchol, Brandacher, Gerald, Alt, Jesse, Majer, Pavel, Volsky, David J, Rais, Rana, Slusher, Barbara S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.08.2017; Amer Chemical Soc
• Subjects: Aminocaproates - administration & dosage; Aminocaproates - chemical synthesis; Aminocaproates - pharmacology; Animals; Azo Compounds - administration & dosage; Azo Compounds - chemical synthesis; Azo Compounds - pharmacology; Blood - metabolism; Brain - metabolism; Chemistry, Medicinal; Diazooxonorleucine - administration & dosage; Diazooxonorleucine - pharmacology; Drug Stability; Female; Glutamic Acid - metabolism; Glutaminase - antagonists & inhibitors; HIV Infections - complications; Humans; Life Sciences & Biomedicine; Male; Mice, Inbred C57BL; Neurocognitive Disorders - drug therapy; Neurocognitive Disorders - etiology; Nootropic Agents - administration & dosage; Nootropic Agents - chemical synthesis; Nootropic Agents - pharmacology; Pharmacology & Pharmacy; Prodrugs - administration & dosage; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Science & Technology; Swine; Viral Load - drug effects; MURINE MODEL; IN-VITRO; MAGNETIC-RESONANCE-SPECTROSCOPY; SYNAPTIC DYSFUNCTION; INDUCE NEUROTOXICITY; COGNITIVE IMPAIRMENT; LONG-TERM POTENTIATION; VIRUS TYPE-1 ENCEPHALITIS; MITOCHONDRIAL GLUTAMINASE; HIV-1-INFECTED MACROPHAGES
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00966

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.