ArticleJournal of medicinal chemistry2017
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.
Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 65 citations in OpenAlex.
- Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.Nature cancer · 2024Trial
- Inhibiting glycan degradation prevents HIV-induced inflammaging and cognitive impairment.Med (New York, N.Y.) · 2026Article
- Recent Nanotherapeutic Advancements Against HIV-Associated Neurocognitive Disorders (HAND).Biomolecules · 2026Review
- A Boronic Acid-Based Glutamine Analog Forms a Covalent Adduct with Kidney-Type Glutaminase and Suppresses Triple-Negative Breast Cancer Cell Proliferation.Biomedicines · 2026Article
- Decoding the Hexosamine Biosynthesis Pathway: Implications for Novel Therapeutic Strategies in Sarcoma.Journal of cellular physiology · 2026Review
- Targeting NAAG metabolism restores cognition and synaptic integrity in EcoHIV-infected mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Inhibiting Glycan Degradation Prevents HIV-Induced Inflammaging and Cognitive Impairment.bioRxiv : the preprint server for biology · 2025Article
- EcoHIV Infection Promotes Atherosclerosis Progression in LDLR-Deficient Mice.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Nicotine and neurocognition in HIV: Translational challenges and therapeutic potential.Neuroscience and biobehavioral reviews · 2025Review
- Energy metabolism in health and diseases.Signal transduction and targeted therapy · 2025Review
- Glutaminase inhibition as potential cancer therapeutics: current status and future applications.Journal of enzyme inhibition and medicinal chemistry · 2024Review
- Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia.Aging and disease · 2024Review
- Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.Acta pharmaceutica Sinica. B · 2024Article
- Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.Cell communication and signaling : CCS · 2024Review
- Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.Nature cancer · 2024Article
- Innate immune responses reverse HIV cognitive disease in mice: Profile by RNAseq in the brain.Virology · 2024Article
- Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor.Molecular cancer therapeutics · 2023Article
- CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice.Scientific reports · 2023Article
- Article
- Synthesis of Novel Kidney-Type Glutaminase Allosteric Inhibitors Targeting the Critical Lys-320 Residue.ACS medicinal chemistry letters · 2023Article
Corrections and comments
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Authors and funding
20 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.