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

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/macrophag...

Full description

Saved in:
Bibliographic Details
Published inJournal 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
LanguageEnglish
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
Online AccessGet full text
ISSN0022-2623
1520-4804
1520-4804
DOI10.1021/acs.jmedchem.7b00966

Cover

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.
AbstractList 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.
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.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.
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.
Author Tenora, Lukás
Furtmüller, Georg
Kelschenbach, Jennifer
Kim, Boe-Hyun
Brandacher, Gerald
Jančařík, Andrej
Chao, Wei
Alt, Jesse
Hadas, Eran
Dash, Ranjeet P
Garrett, Caroline
Majer, Pavel
Rais, Rana
Gadiano, Alexandra J
Nedelcovych, Michael T
Oh, Byoungchol
Volsky, David J
Slusher, Barbara S
Zimmermann, Sarah C
Prchalová, Eva
AuthorAffiliation Medicine
Academy of Sciences of the Czech Republic vvi
Neuroscience
Molecular and Comparative Pathobiology
Institute of Organic Chemistry and Biochemistry
Johns Hopkins Drug Discovery
Oncology
Department of Medicine
Departments of Neurology
Psychiatry
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery
Johns Hopkins School of Medicine
AuthorAffiliation_xml – name: Institute of Organic Chemistry and Biochemistry
– name: Johns Hopkins School of Medicine
– name: Department of Medicine
– name: Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery
– name: Neuroscience
– name: Academy of Sciences of the Czech Republic vvi
– name: Psychiatry
– name: Johns Hopkins Drug Discovery
– name: Oncology
– name: Departments of Neurology
– name: Medicine
– name: Molecular and Comparative Pathobiology
– name: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic vvi, 166 10 Prague, Czech Republic
– name: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
– name: Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
– name: Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
Author_xml – sequence: 1
  givenname: Michael T
  surname: Nedelcovych
  fullname: Nedelcovych, Michael T
– sequence: 2
  givenname: Lukáš
  surname: Tenora
  fullname: Tenora, Lukáš
  organization: Academy of Sciences of the Czech Republic vvi
– sequence: 3
  givenname: Boe-Hyun
  surname: Kim
  fullname: Kim, Boe-Hyun
  organization: Department of Medicine
– sequence: 4
  givenname: Jennifer
  surname: Kelschenbach
  fullname: Kelschenbach, Jennifer
  organization: Department of Medicine
– sequence: 5
  givenname: Wei
  surname: Chao
  fullname: Chao, Wei
  organization: Department of Medicine
– sequence: 6
  givenname: Eran
  surname: Hadas
  fullname: Hadas, Eran
  organization: Department of Medicine
– sequence: 7
  givenname: Andrej
  surname: Jančařík
  fullname: Jančařík, Andrej
  organization: Academy of Sciences of the Czech Republic vvi
– sequence: 8
  givenname: Eva
  surname: Prchalová
  fullname: Prchalová, Eva
  organization: Academy of Sciences of the Czech Republic vvi
– sequence: 9
  givenname: Sarah C
  surname: Zimmermann
  fullname: Zimmermann, Sarah C
– sequence: 10
  givenname: Ranjeet P
  surname: Dash
  fullname: Dash, Ranjeet P
– sequence: 11
  givenname: Alexandra J
  surname: Gadiano
  fullname: Gadiano, Alexandra J
– sequence: 12
  givenname: Caroline
  surname: Garrett
  fullname: Garrett, Caroline
– sequence: 13
  givenname: Georg
  surname: Furtmüller
  fullname: Furtmüller, Georg
– sequence: 14
  givenname: Byoungchol
  surname: Oh
  fullname: Oh, Byoungchol
– sequence: 15
  givenname: Gerald
  surname: Brandacher
  fullname: Brandacher, Gerald
– sequence: 16
  givenname: Jesse
  surname: Alt
  fullname: Alt, Jesse
– sequence: 17
  givenname: Pavel
  surname: Majer
  fullname: Majer, Pavel
  email: majer@uochb.cas.cz
  organization: Academy of Sciences of the Czech Republic vvi
– sequence: 18
  givenname: David J
  surname: Volsky
  fullname: Volsky, David J
  email: david.volsky@mssm.edu
  organization: Department of Medicine
– sequence: 19
  givenname: Rana
  orcidid: 0000-0003-4059-2453
  surname: Rais
  fullname: Rais, Rana
  email: rrais2@jhmi.edu
– sequence: 20
  givenname: Barbara S
  orcidid: 0000-0001-9814-4157
  surname: Slusher
  fullname: Slusher, Barbara S
  email: bslusher@jhmi.edu
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28759224$$D View this record in MEDLINE/PubMed
BookMark eNqNUstuEzEUHaEi-oA_QMjLVGiC7ZnxeFggRQm0lao0i8J25PF4EhfHt7U9oWHFL_Ap_BJfgkPSCFgAC8u6uueca99zjpMDC1YlyXOChwRT8kpIP7xZqlYu1HJYNhhXjD1KjkhBcZpznB8kRxhTmlJGs8Pk2PsbjHFGaPYkOaS8LCpK86Pk2_T7l6-DmV4JA2sD9-tTYT7GK5XCNWDXBs0ctK6fewQdCguFzkwfxFJbhUY2iDlY7QNiUWWixWdIixTuIVYmHgvOqF5usIPJ1fQUCY8EmkFQNmhh0LVTIixjgTpw6PziAxp5D1KLoFo0Vb0DCXOrg14pNNEeXKucf5o87oTx6tnuPknev3t7PT5PL6_OLsajy1TkeRXSjBeKNpWqSM5ZTiljJSkZLXiBJW8Jl7igLa4koVUmyxazWPGGCNKVDSelzE6SN1vd277ZrDk-0wlT3zq9FG5dg9D17x2rF_UcVnVRVgWjOAoMdgIO7nrlQ73UXipjhFXQ-5pUtKCcEMYi9MWvs_ZDHnyKgJdbwCfVQOelVlaqPSwam2NeVPFv0fINmv8_eqyDCBrsGHobIjXfUqUD753q9jSC603u6pi7-iF39S53kfb6D5rcycbVaPMvMt6Sf3ahdzb6-nfKD2D790Y
CitedBy_id crossref_primary_10_1016_j_critrevonc_2021_103227
crossref_primary_10_1016_j_bbih_2022_100478
crossref_primary_10_1016_j_ejmech_2022_115014
crossref_primary_10_1073_pnas_1812909115
crossref_primary_10_1038_s41598_019_45878_6
crossref_primary_10_3233_JAD_190588
crossref_primary_10_3390_cancers14051311
crossref_primary_10_1002_JLB_5AB0420_531R
crossref_primary_10_3389_fcimb_2020_00261
crossref_primary_10_1158_1535_7163_MCT_23_0258
crossref_primary_10_1007_s11481_019_09859_w
crossref_primary_10_3390_cells12040632
crossref_primary_10_1021_acs_jmedchem_8b02009
crossref_primary_10_14336_AD_2023_0311
crossref_primary_10_1093_noajnl_vdaa149
crossref_primary_10_1007_s00335_021_09907_y
crossref_primary_10_1038_s41392_025_02141_x
crossref_primary_10_1016_j_cej_2023_148281
crossref_primary_10_1042_CS20201042
crossref_primary_10_1097_QAD_0000000000002150
crossref_primary_10_1158_1535_7163_MCT_19_0319
crossref_primary_10_1212_NXI_0000000000000609
crossref_primary_10_1016_j_bbih_2020_100054
crossref_primary_10_1158_1535_7163_MCT_17_1148
crossref_primary_10_1016_j_nbd_2022_105734
crossref_primary_10_1039_D2CS00957A
crossref_primary_10_1016_j_bmcl_2021_128321
crossref_primary_10_1080_14756366_2023_2290911
crossref_primary_10_1186_s12964_023_01449_x
crossref_primary_10_1021_acs_molpharmaceut_9b00637
crossref_primary_10_1093_jnen_nlab018
crossref_primary_10_1096_fj_201901874R
crossref_primary_10_1128_mBio_00591_19
crossref_primary_10_1016_j_bbi_2020_11_038
crossref_primary_10_1186_s12987_020_00204_5
crossref_primary_10_3389_fimmu_2022_1004985
crossref_primary_10_1038_s43018_023_00649_1
crossref_primary_10_1172_jci_insight_121000
crossref_primary_10_1038_s43018_024_00811_3
crossref_primary_10_1038_s42003_021_02985_3
crossref_primary_10_3390_metabo11020112
crossref_primary_10_1021_acsmedchemlett_2c00302
crossref_primary_10_1038_s41598_023_33491_7
crossref_primary_10_1016_j_virol_2023_109917
crossref_primary_10_1126_sciadv_abq5925
crossref_primary_10_3389_fonc_2020_589508
crossref_primary_10_1021_acs_jmedchem_8b00961
crossref_primary_10_3390_ijms24010012
crossref_primary_10_1038_s41386_018_0177_7
crossref_primary_10_1016_j_ejmech_2019_111878
crossref_primary_10_1371_journal_ppat_1007061
crossref_primary_10_3390_ijms23105572
crossref_primary_10_1016_j_apsb_2023_10_020
Cites_doi 10.1007/s13365-014-0258-2
10.1016/j.lfs.2009.03.013
10.1212/WNL.56.1.112
10.1007/s11481-006-9062-y
10.1073/pnas.0500649102
10.1371/journal.pone.0076581
10.1128/JVI.01045-16
10.1002/1097-0142(195711/12)10:6<1138::AID-CNCR2820100608>3.0.CO;2-K
10.1111/j.1471-4159.2009.05989.x
10.1002/med.21252
10.1002/1520-6017(200008)89:8<1054::AID-JPS10>3.0.CO;2-5
10.1523/JNEUROSCI.2051-11.2011
10.1016/S0306-4522(02)00925-9
10.1371/journal.pone.0032995
10.1016/j.biopsych.2012.09.026
10.1016/j.ab.2015.01.001
10.1097/QAD.0b013e32828e4e27
10.1620/tjem.217.87
10.1371/journal.ppat.1002213
10.1007/s11095-012-0911-5
10.1177/42.6.7910617
10.1007/s13365-015-0314-6
10.1124/dmd.112.046821
10.1093/cercor/bhp274
10.1016/j.celrep.2015.09.036
10.1016/j.brainres.2004.03.037
10.1111/j.1471-4159.2007.04594.x
10.1111/j.1471-4159.2007.05197.x
10.1111/1348-0421.12266
10.1097/NEN.0000000000000026
10.1007/s11481-013-9442-z
10.1002/jps.21047
10.1097/QAD.0b013e3283427da7
10.1007/BF00216936
10.1186/s12883-016-0628-x
10.1007/s11481-012-9345-4
10.1002/jps.20542
10.1007/BF00170760
10.1016/j.cnr.2006.09.009
10.1021/acs.jmedchem.6b01069
10.1002/jmri.22366
10.1016/j.mri.2010.06.007
10.1089/10445490152717604
10.1016/j.bbrc.2013.11.043
10.1111/jnc.12263
10.1097/QAD.0000000000000303
10.1016/j.virol.2017.05.013
10.1007/s11481-011-9316-1
10.1212/WNL.0b013e318200d727
10.1097/QAD.0b013e3281574549
10.1002/jps.24632
10.1523/JNEUROSCI.1933-04.2004
10.1007/s11481-009-9161-7
10.1371/journal.pone.0046178
10.1097/QAD.0b013e32813384e8
10.1046/j.1471-4159.2003.02146.x
10.1098/rspb.1984.0028
10.1016/S0378-5173(00)00507-X
10.1002/nbm.1329
10.1007/s11065-009-9102-5
10.1002/jnr.20745
10.1007/s11094-009-0213-3
10.1007/s11481-012-9364-1
10.1007/s13365-010-0006-1
10.1186/s13024-015-0058-z
10.1208/s12248-008-9009-8
10.1002/ana.10844
10.1097/NEN.0000000000000024
ContentType Journal Article
Copyright Copyright © 2017 American Chemical Society
Copyright_xml – notice: Copyright © 2017 American Chemical Society
DBID AAYXX
CITATION
17B
1KM
BLEPL
DTL
EGQ
GYRTJ
CGR
CUY
CVF
ECM
EIF
NPM
7X8
5PM
DOI 10.1021/acs.jmedchem.7b00966
DatabaseName CrossRef
Web of Knowledge
Index Chemicus
Web of Science Core Collection
Science Citation Index Expanded
Web of Science Primary (SCIE, SSCI & AHCI)
Web of Science - Science Citation Index Expanded - 2017
Medline
MEDLINE
MEDLINE (Ovid)
MEDLINE
MEDLINE
PubMed
MEDLINE - Academic
PubMed Central (Full Participant titles)
DatabaseTitle CrossRef
Web of Science
MEDLINE
Medline Complete
MEDLINE with Full Text
PubMed
MEDLINE (Ovid)
MEDLINE - Academic
DatabaseTitleList
MEDLINE
MEDLINE - Academic
Web of Science
Database_xml – sequence: 1
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 2
  dbid: 1KM
  name: Index Chemicus
  url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/woscc/search-with-editions?editions=WOS.IC
  sourceTypes:
    Enrichment Source
    Index Database
DeliveryMethod fulltext_linktorsrc
Discipline Chemistry
Pharmacy, Therapeutics, & Pharmacology
EISSN 1520-4804
EndPage 7198
ExternalDocumentID PMC5795620
28759224
000408598500024
10_1021_acs_jmedchem_7b00966
a091375605
Genre Journal Article
GrantInformation_xml – fundername: NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
  grantid: R01MH104145
– fundername: NIDA NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA)
  grantid: R01 DA037611
– fundername: NIMH NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
  grantid: P30 MH075673; R01 MH104145; P01 MH105280
– fundername: NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission
  grantid: R01DA037611
– fundername: NIMH NIH HHS
  grantid: P01 MH105280
– fundername: NIMH NIH HHS
  grantid: P30 MH075673
– fundername: NIDA NIH HHS
  grantid: R01 DA037611
– fundername: NIMH NIH HHS
  grantid: R01 MH104145
– fundername: NCI NIH HHS
  grantid: R01 CA193895
GroupedDBID -
.K2
55A
5GY
5RE
5VS
7~N
AABXI
ABFLS
ABMVS
ABOCM
ABPTK
ABUCX
ACGFS
ACJ
ACS
AEESW
AENEX
AFEFF
ALMA_UNASSIGNED_HOLDINGS
AQSVZ
BAANH
CS3
DU5
EBS
ED
ED~
EJD
F5P
GNL
IH9
IHE
JG
JG~
K2
L7B
LG6
P2P
ROL
TN5
UI2
VF5
VG9
W1F
WH7
X
XFK
YZZ
ZY4
---
-~X
4.4
6P2
AAHBH
AAYXX
ABBLG
ABJNI
ABLBI
ABQRX
ACGFO
ADHLV
AGXLV
AHGAQ
CITATION
CUPRZ
GGK
IH2
XSW
YQT
17B
1KM
BLEPL
DTL
GROUPED_WOS_SCIENCE_CITATION_INDEX_EXPANDED
GROUPED_WOS_WEB_OF_SCIENCE
CGR
CUY
CVF
ECM
EIF
NPM
7X8
5PM
ID FETCH-LOGICAL-a449t-385e2b9e9148642266717625850c8d18c052d09c1293c7d062d08b1a1f7b817c3
IEDL.DBID ACS
ISICitedReferencesCount 56
ISICitedReferencesURI https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=CitingArticles&UT=000408598500024
ISSN 0022-2623
1520-4804
IngestDate Tue Sep 30 16:45:36 EDT 2025
Fri Jul 11 10:06:24 EDT 2025
Mon Jul 21 05:56:52 EDT 2025
Wed Jul 09 09:16:25 EDT 2025
Fri Sep 26 20:25:43 EDT 2025
Tue Jul 01 00:42:52 EDT 2025
Thu Apr 24 23:03:53 EDT 2025
Thu Aug 27 13:42:24 EDT 2020
IsDoiOpenAccess false
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 16
Keywords 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
Language English
LinkModel DirectLink
LogoURL https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg
MergedId FETCHMERGED-LOGICAL-a449t-385e2b9e9148642266717625850c8d18c052d09c1293c7d062d08b1a1f7b817c3
Notes Medline
NIH RePORTER
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
M.T.N. and L.T. contributed equally
Author Contributions
ORCID 0000-0003-4059-2453
0000-0001-9814-4157
0000-0002-6944-1002
0000-0001-7790-441X
OpenAccessLink https://www.ncbi.nlm.nih.gov/pmc/articles/5795620
PMID 28759224
PQID 1925281166
PQPubID 23479
PageCount 13
ParticipantIDs crossref_primary_10_1021_acs_jmedchem_7b00966
webofscience_primary_000408598500024CitationCount
pubmed_primary_28759224
proquest_miscellaneous_1925281166
webofscience_primary_000408598500024
pubmedcentral_primary_oai_pubmedcentral_nih_gov_5795620
acs_journals_10_1021_acs_jmedchem_7b00966
crossref_citationtrail_10_1021_acs_jmedchem_7b00966
ProviderPackageCode JG~
55A
AABXI
GNL
VF5
7~N
ACJ
VG9
W1F
ACS
AEESW
AFEFF
.K2
ABMVS
ABUCX
IH9
BAANH
AQSVZ
ED~
UI2
CITATION
AAYXX
PublicationCentury 2000
PublicationDate 2017-08-24
PublicationDateYYYYMMDD 2017-08-24
PublicationDate_xml – month: 08
  year: 2017
  text: 2017-08-24
  day: 24
PublicationDecade 2010
PublicationPlace WASHINGTON
PublicationPlace_xml – name: WASHINGTON
– name: United States
PublicationTitle Journal of medicinal chemistry
PublicationTitleAbbrev J MED CHEM
PublicationTitleAlternate J. Med. Chem
PublicationYear 2017
Publisher American Chemical Society
Amer Chemical Soc
Publisher_xml – name: American Chemical Society
– name: Amer Chemical Soc
References ref9/cit9
ref45/cit45
ref3/cit3
ref27/cit27
ref63/cit63
ref56/cit56
ref16/cit16
ref52/cit52
ref23/cit23
ref8/cit8
ref31/cit31
ref59/cit59
ref2/cit2
ref34/cit34
ref71/cit71
ref37/cit37
ref20/cit20
ref48/cit48
ref60/cit60
ref74/cit74
ref17/cit17
ref10/cit10
ref35/cit35
ref53/cit53
ref19/cit19
ref21/cit21
ref42/cit42
ref46/cit46
ref49/cit49
ref13/cit13
ref61/cit61
ref67/cit67
ref24/cit24
ref38/cit38
ref64/cit64
ref54/cit54
ref6/cit6
ref36/cit36
ref18/cit18
ref65/cit65
ref11/cit11
ref25/cit25
ref29/cit29
ref72/cit72
ref32/cit32
ref39/cit39
ref14/cit14
ref57/cit57
ref5/cit5
ref51/cit51
ref43/cit43
ref28/cit28
ref40/cit40
ref68/cit68
ref26/cit26
ref55/cit55
ref73/cit73
ref69/cit69
ref12/cit12
ref15/cit15
ref62/cit62
ref66/cit66
ref41/cit41
ref58/cit58
ref22/cit22
ref33/cit33
ref4/cit4
ref30/cit30
Fattash B. (ref50/cit50) 2014
ref47/cit47
ref1/cit1
Baranczewski P. (ref75/cit75) 2006; 58
ref44/cit44
ref70/cit70
ref7/cit7
Zhao, LX (WOS:000325025200077) 2013; 8
Cassol, E (WOS:000338645000004) 2014; 28
Huang, YL (WOS:000296274000039) 2011; 31
Zhao, LX (WOS:000305339100028) 2012; 7
Fitting, S (WOS:000314634900010) 2013; 73
Van Gelder, J (WOS:000089711400009) 2000; 205
Keblesh, JP (WOS:000268583500004) 2009; 4
Ye, L (WOS:000320041700010) 2013; 125
Tian, CH (WOS:000307556000014) 2012; 7
MAGILL, GB (WOS:A1957WC23400007) 1957; 10
Schifitto, G (WOS:000249645000007) 2007; 21
Stankoff, B (WOS:000166286500023) 2001; 56
Anderson, ER (WOS:000182532600007) 2003; 118
Vlieghe, P (WOS:000317616000001) 2013; 33
Heaton, RK (WOS:000285044300011) 2010; 75
Tian, CH (WOS:000255139200038) 2008; 105
Li, FJ (WOS:000253557400008) 2008; 97
Annaert, P (WOS:000088733500010) 2000; 89
Behnisch, T (WOS:000222063500023) 2004; 1012
Gelman, BB (WOS:000307556000020) 2012; 7
Wu, BQ (WOS:000364629200001) 2015; 10
Sailasuta, N (WOS:000264578200011) 2009; 22
CHUNG, SH (WOS:A1984SP59700002) 1984; 221
Erdmann, NB (WOS:000243814000008) 2006; 6
Rais, R (WOS:000384035300029) 2016; 59
Woods, SP (WOS:000266665400003) 2009; 19
Ernst, T (WOS:000284190200004) 2010; 32
RAHMAN, A (WOS:A1985AWP1200008) 1985; 3
Dong, J (WOS:000235528000014) 2006; 83
(000408598500024.58) 2008
Heaton, RK (WOS:000289580200002) 2011; 17
Anderson, ER (WOS:000223331100017) 2004; 24
Musante, V (WOS:000280597100020) 2010; 20
CONTI, F (WOS:A1994NN03400003) 1994; 42
Erdmann, N (WOS:000247581300023) 2007; 102
Gelman, BB (WOS:000309517300094) 2012; 7
Vazquez-Santiago, FJ (WOS:000339331700001) 2014; 20
Tang, HM (WOS:000267185200001) 2009; 85
Potash, MJ (WOS:000227533100044) 2005; 102
Rasheed, A. (000408598500024.48) 2008; 42
Harezlak, J (WOS:000287963600011) 2011; 25
Thomas, AG (WOS:000330485900007) 2014; 443
Zink, MC (WOS:000248869500004) 2007; 2
Erdmann, N (WOS:000264345900024) 2009; 109
Liederer, BM (WOS:000237937300002) 2006; 95
Doi, A (WOS:000358368300005) 2015; 59
EARHART, RH (WOS:A1990CR84100019) 1990; 8
Muscarella, LA (WOS:000335647400005) 2014; 73
Lee, CF (WOS:000363780900012) 2015; 13
Fu, J (WOS:000381768500067) 2016; 105
Robertson, KR (WOS:000249645000011) 2007; 21
(000408598500024.59) 2006
Fattash, B., Pharmacology-Research, Safety Testing and Regulation (000408598500024.50) 2014
Suenderhauf, C (WOS:000312637300001) 2013; 30
Borjabad, A (WOS:000295409000018) 2011; 7
Potter, MC (WOS:000320312300014) 2013; 8
Mohamed, MA (WOS:000283906800001) 2010; 28
(000408598500024.64) 2013
Baxter, VK (WOS:000404077500015) 2017; 508
(000408598500024.57) 2005
Rautio, J (WOS:000255198200010) 2008; 10
Li, ST (WOS:000189275800008) 2004; 55
Bairwa, D (WOS:000379740400003) 2016; 16
Zhao, JX (WOS:000187275700018) 2004; 88
References_xml – ident: ref7/cit7
  doi: 10.1007/s13365-014-0258-2
– ident: ref28/cit28
  doi: 10.1016/j.lfs.2009.03.013
– ident: ref35/cit35
  doi: 10.1212/WNL.56.1.112
– ident: ref1/cit1
  doi: 10.1007/s11481-006-9062-y
– ident: ref42/cit42
  doi: 10.1073/pnas.0500649102
– ident: ref19/cit19
  doi: 10.1371/journal.pone.0076581
– ident: ref67/cit67
  doi: 10.1128/JVI.01045-16
– ident: ref45/cit45
  doi: 10.1002/1097-0142(195711/12)10:6<1138::AID-CNCR2820100608>3.0.CO;2-K
– ident: ref9/cit9
  doi: 10.1111/j.1471-4159.2009.05989.x
– ident: ref53/cit53
  doi: 10.1002/med.21252
– ident: ref63/cit63
  doi: 10.1002/1520-6017(200008)89:8<1054::AID-JPS10>3.0.CO;2-5
– ident: ref12/cit12
  doi: 10.1523/JNEUROSCI.2051-11.2011
– ident: ref21/cit21
  doi: 10.1016/S0306-4522(02)00925-9
– ident: ref18/cit18
  doi: 10.1371/journal.pone.0032995
– ident: ref25/cit25
  doi: 10.1016/j.biopsych.2012.09.026
– ident: ref69/cit69
  doi: 10.1016/j.ab.2015.01.001
– ident: ref58/cit58
– ident: ref5/cit5
  doi: 10.1097/QAD.0b013e32828e4e27
– ident: ref66/cit66
  doi: 10.1620/tjem.217.87
– ident: ref38/cit38
  doi: 10.1371/journal.ppat.1002213
– ident: ref56/cit56
  doi: 10.1007/s11095-012-0911-5
– ident: ref39/cit39
  doi: 10.1177/42.6.7910617
– ident: ref68/cit68
  doi: 10.1007/s13365-015-0314-6
– ident: ref74/cit74
  doi: 10.1124/dmd.112.046821
– ident: ref20/cit20
  doi: 10.1093/cercor/bhp274
– start-page: 103
  volume-title: Prodrugs Design–A New Era
  year: 2014
  ident: ref50/cit50
– ident: ref61/cit61
  doi: 10.1016/j.celrep.2015.09.036
– ident: ref23/cit23
  doi: 10.1016/j.brainres.2004.03.037
– ident: ref64/cit64
– ident: ref10/cit10
  doi: 10.1111/j.1471-4159.2007.04594.x
– ident: ref14/cit14
  doi: 10.1111/j.1471-4159.2007.05197.x
– ident: ref8/cit8
  doi: 10.1111/1348-0421.12266
– ident: ref43/cit43
  doi: 10.1097/NEN.0000000000000026
– ident: ref6/cit6
  doi: 10.1007/s11481-013-9442-z
– ident: ref49/cit49
  doi: 10.1002/jps.21047
– ident: ref3/cit3
  doi: 10.1097/QAD.0b013e3283427da7
– volume: 58
  start-page: 453
  year: 2006
  ident: ref75/cit75
  publication-title: Pharmacol. Rep.
– ident: ref44/cit44
  doi: 10.1007/BF00216936
– ident: ref30/cit30
  doi: 10.1186/s12883-016-0628-x
– ident: ref37/cit37
  doi: 10.1007/s11481-012-9345-4
– ident: ref59/cit59
– ident: ref51/cit51
  doi: 10.1002/jps.20542
– ident: ref46/cit46
  doi: 10.1007/BF00170760
– ident: ref11/cit11
  doi: 10.1016/j.cnr.2006.09.009
– ident: ref47/cit47
  doi: 10.1021/acs.jmedchem.6b01069
– ident: ref31/cit31
  doi: 10.1002/jmri.22366
– ident: ref32/cit32
  doi: 10.1016/j.mri.2010.06.007
– ident: ref70/cit70
  doi: 10.1089/10445490152717604
– ident: ref13/cit13
  doi: 10.1016/j.bbrc.2013.11.043
– ident: ref17/cit17
  doi: 10.1111/jnc.12263
– ident: ref57/cit57
– ident: ref29/cit29
  doi: 10.1097/QAD.0000000000000303
– ident: ref62/cit62
  doi: 10.1016/j.virol.2017.05.013
– ident: ref73/cit73
  doi: 10.1007/s11481-011-9316-1
– ident: ref65/cit65
  doi: 10.1073/pnas.0500649102
– ident: ref2/cit2
  doi: 10.1212/WNL.0b013e318200d727
– ident: ref71/cit71
  doi: 10.1097/QAD.0b013e3281574549
– ident: ref54/cit54
  doi: 10.1002/jps.24632
– ident: ref22/cit22
  doi: 10.1523/JNEUROSCI.1933-04.2004
– ident: ref26/cit26
  doi: 10.1007/s11481-009-9161-7
– ident: ref36/cit36
  doi: 10.1371/journal.pone.0046178
– ident: ref72/cit72
  doi: 10.1097/NEN.0000000000000026
– ident: ref34/cit34
  doi: 10.1097/QAD.0b013e32813384e8
– ident: ref41/cit41
  doi: 10.1046/j.1471-4159.2003.02146.x
– ident: ref40/cit40
  doi: 10.1098/rspb.1984.0028
– ident: ref55/cit55
  doi: 10.1016/S0378-5173(00)00507-X
– ident: ref33/cit33
  doi: 10.1002/nbm.1329
– ident: ref60/cit60
  doi: 10.1007/s11065-009-9102-5
– ident: ref24/cit24
  doi: 10.1002/jnr.20745
– ident: ref48/cit48
  doi: 10.1007/s11094-009-0213-3
– ident: ref15/cit15
  doi: 10.1007/s11481-012-9364-1
– ident: ref4/cit4
  doi: 10.1007/s13365-010-0006-1
– ident: ref16/cit16
  doi: 10.1186/s13024-015-0058-z
– ident: ref52/cit52
  doi: 10.1208/s12248-008-9009-8
– ident: ref27/cit27
  doi: 10.1002/ana.10844
– start-page: 103
  year: 2014
  ident: 000408598500024.50
  article-title: Chemical approaches used in prodrugs design
  publication-title: Prodrugs Design-A New Era
– volume: 3
  start-page: 369
  year: 1985
  ident: WOS:A1985AWP1200008
  article-title: PHASE-I STUDY AND CLINICAL-PHARMACOLOGY OF 6-DIAZO-5-OXO-L-NORLEUCINE (DON)
  publication-title: INVESTIGATIONAL NEW DRUGS
– volume: 88
  start-page: 169
  year: 2004
  ident: WOS:000187275700018
  article-title: Mitochondrial glutaminase enhances extracellular glutamate production in HIV-1-infected macrophages: Linkage to HIV-1 associated dementia
  publication-title: JOURNAL OF NEUROCHEMISTRY
  doi: 10.1046/j.1471-4159.2003.02146.x
– volume: 56
  start-page: 112
  year: 2001
  ident: WOS:000166286500023
  article-title: Clinical and spectroscopic improvement in HIV-associated cognitive impairment
  publication-title: NEUROLOGY
– volume: 2
  start-page: 14
  year: 2007
  ident: WOS:000248869500004
  article-title: Translational research models and novel adjunctive therapies for neuroAIDS
  publication-title: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
  doi: 10.1007/s11481-006-9062-y
– volume: 221
  start-page: 145
  year: 1984
  ident: WOS:A1984SP59700002
  article-title: STUDIES ON SOUND-INDUCED EPILEPSY IN MICE
  publication-title: PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES
– volume: 13
  start-page: 760
  year: 2015
  ident: WOS:000363780900012
  article-title: Preventing Allograft Rejection by Targeting Immune Metabolism
  publication-title: CELL REPORTS
  doi: 10.1016/j.celrep.2015.09.036
– volume: 30
  start-page: 1
  year: 2013
  ident: WOS:000312637300001
  article-title: A Physiologically Based Pharmacokinetic Model of the Minipig: Data Compilation and Model Implementation
  publication-title: PHARMACEUTICAL RESEARCH
  doi: 10.1007/s11095-012-0911-5
– volume: 1012
  start-page: 187
  year: 2004
  ident: WOS:000222063500023
  article-title: HIV secreted protein Tat prevents long-term potentiation in the hippocampal CA1 region
  publication-title: BRAIN RESEARCH
  doi: 10.1016/j.brainres.2004.03.037
– volume: 42
  start-page: 717
  year: 1994
  ident: WOS:A1994NN03400003
  article-title: GLUTAMATE IMMUNOREACTIVITY IN RAT CEREBRAL-CORTEX IS REVERSIBLY ABOLISHED BY 6-DIAZO-5-OXO-L-NORLEUCINE (DON), AN INHIBITOR OF PHOSPHATE-ACTIVATED GLUTAMINASE
  publication-title: JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY
– volume: 28
  start-page: 1251
  year: 2010
  ident: WOS:000283906800001
  article-title: Brain metabolism and cognitive impairment in HIV infection: a 3-T magnetic resonance spectroscopy study
  publication-title: MAGNETIC RESONANCE IMAGING
  doi: 10.1016/j.mri.2010.06.007
– volume: 20
  start-page: 1974
  year: 2010
  ident: WOS:000280597100020
  article-title: The HIV-1 Viral Protein Tat Increases Glutamate and Decreases GABA Exocytosis from Human and Mouse Neocortical Nerve Endings
  publication-title: CEREBRAL CORTEX
  doi: 10.1093/cercor/bhp274
– volume: 55
  start-page: 362
  year: 2004
  ident: WOS:000189275800008
  article-title: HIV-1 inhibits long-term potentiation and attenuates spatial learning
  publication-title: ANNALS OF NEUROLOGY
  doi: 10.1002/ana.10844
– volume: 7
  start-page: 686
  year: 2012
  ident: WOS:000307556000020
  article-title: Prefrontal Dopaminergic and Enkephalinergic Synaptic Accommodation in HIV-associated Neurocognitive Disorders and Encephalitis
  publication-title: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
  doi: 10.1007/s11481-012-9345-4
– volume: 6
  start-page: 315
  year: 2006
  ident: WOS:000243814000008
  article-title: Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase
  publication-title: CLINICAL NEUROSCIENCE RESEARCH
  doi: 10.1016/j.cnr.2006.09.009
– volume: 31
  start-page: 15195
  year: 2011
  ident: WOS:000296274000039
  article-title: Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders
  publication-title: JOURNAL OF NEUROSCIENCE
  doi: 10.1523/JNEUROSCI.2051-11.2011
– volume: 75
  start-page: 2087
  year: 2010
  ident: WOS:000285044300011
  article-title: HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy CHARTER Study
  publication-title: NEUROLOGY
– volume: 443
  start-page: 32
  year: 2014
  ident: WOS:000330485900007
  article-title: Small molecule glutaminase inhibitors block glutamate release from stimulated microglia
  publication-title: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
  doi: 10.1016/j.bbrc.2013.11.043
– volume: 7
  start-page: ARTN e32995
  year: 2012
  ident: WOS:000305339100028
  article-title: Interferon-alpha Regulates Glutaminase 1 Promoter through STAT1 Phosphorylation: Relevance to HIV-1 Associated Neurocognitive Disorders
  publication-title: PLOS ONE
  doi: 10.1371/journal.pone.0032995
– volume: 7
  start-page: ARTN e1002213
  year: 2011
  ident: WOS:000295409000018
  article-title: Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-1-Associated Neurocognitive Disorders
  publication-title: PLOS PATHOGENS
  doi: 10.1371/journal.ppat.1002213
– volume: 24
  start-page: 7194
  year: 2004
  ident: WOS:000223331100017
  article-title: Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis
  publication-title: JOURNAL OF NEUROSCIENCE
  doi: 10.1523/JNEUROSCI.1933-04.2004
– volume: 21
  start-page: 1915
  year: 2007
  ident: WOS:000249645000011
  article-title: The prevalence and incidence of neurocognitive impairment in the HAART era
  publication-title: AIDS
– volume: 21
  start-page: 1877
  year: 2007
  ident: WOS:000249645000007
  article-title: Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study
  publication-title: AIDS
– volume: 42
  start-page: 677
  year: 2008
  ident: 000408598500024.48
  article-title: Novel approaches on prodrug baseddrug design
  publication-title: Pharm. Chem. J.
– volume: 33
  start-page: 457
  year: 2013
  ident: WOS:000317616000001
  article-title: Medicinal Chemistry Based Approaches and Nanotechnology-Based Systems to Improve CNS Drug Targeting and Delivery
  publication-title: MEDICINAL RESEARCH REVIEWS
  doi: 10.1002/med.21252
– volume: 85
  start-page: 1
  year: 2009
  ident: WOS:000267185200001
  article-title: Curcumin improves spatial memory impairment induced by human immunodeficiency virus type 1 glycoprotein 120 V3 loop peptide in rats
  publication-title: LIFE SCIENCES
  doi: 10.1016/j.lfs.2009.03.013
– volume: 97
  start-page: 1109
  year: 2008
  ident: WOS:000253557400008
  article-title: Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting
  publication-title: JOURNAL OF PHARMACEUTICAL SCIENCES
  doi: 10.1002/jps.21047
– volume: 10
  start-page: 92
  year: 2008
  ident: WOS:000255198200010
  article-title: Prodrug approaches for CNS delivery
  publication-title: AAPS JOURNAL
  doi: 10.1208/s12248-008-9009-8
– volume: 22
  start-page: 326
  year: 2009
  ident: WOS:000264578200011
  article-title: Evidence of reduced glutamate in the frontal lobe of HIV-seropositive patients
  publication-title: NMR IN BIOMEDICINE
  doi: 10.1002/nbm.1329
– year: 2013
  ident: 000408598500024.64
  article-title: Method for Promoting the Synthesis of Collagen and Proteoglycan in Chondrocytes
  publication-title: U.S. Pat. Appl.
– volume: 7
  start-page: ARTN e46178
  year: 2012
  ident: WOS:000309517300094
  article-title: The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment
  publication-title: PLOS ONE
  doi: 10.1371/journal.pone.0046178
– volume: 83
  start-page: 489
  year: 2006
  ident: WOS:000235528000014
  article-title: Human immunodeficiency virus type 1 gp120 inhibits long-term potentiation via chemokine receptor CXCR4 in rat hippocampal slices
  publication-title: JOURNAL OF NEUROSCIENCE RESEARCH
  doi: 10.1002/jnr.20745
– volume: 20
  start-page: 315
  year: 2014
  ident: WOS:000339331700001
  article-title: Glutamate metabolism and HIV-associated neurocognitive disorders
  publication-title: JOURNAL OF NEUROVIROLOGY
  doi: 10.1007/s13365-014-0258-2
– volume: 105
  start-page: 994
  year: 2008
  ident: WOS:000255139200038
  article-title: HIV-infected macrophages mediate neuronal apoptosis through mitochondrial glutaminase
  publication-title: JOURNAL OF NEUROCHEMISTRY
  doi: 10.1111/j.1471-4159.2007.05197.x
– volume: 59
  start-page: 8621
  year: 2016
  ident: WOS:000384035300029
  article-title: Discovery of 6-Diazo-5-oxo-L-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/acs.jmedchem.6b01069
– year: 2006
  ident: 000408598500024.59
  article-title: Prodrugs of GABA Analogs, Compositions and Uses Thereof
  publication-title: U.S. Pat. Appl.
– volume: 125
  start-page: 897
  year: 2013
  ident: WOS:000320041700010
  article-title: IL-1 and TNF- induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase
  publication-title: JOURNAL OF NEUROCHEMISTRY
  doi: 10.1111/jnc.12263
– volume: 32
  start-page: 1045
  year: 2010
  ident: WOS:000284190200004
  article-title: Lower Brain Glutamate Is Associated With Cognitive Deficits in HIV Patients: A New Mechanism for HIV-Associated Neurocognitive Disorder
  publication-title: JOURNAL OF MAGNETIC RESONANCE IMAGING
  doi: 10.1002/jmri.22366
– volume: 59
  start-page: 398
  year: 2015
  ident: WOS:000358368300005
  article-title: Viral protein R of HIV type-1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway
  publication-title: MICROBIOLOGY AND IMMUNOLOGY
  doi: 10.1111/1348-0421.12266
– volume: 4
  start-page: 317
  year: 2009
  ident: WOS:000268583500004
  article-title: 4-Aminopyridine Improves Spatial Memory in a Murine Model of HIV-1 Encephalitis
  publication-title: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
  doi: 10.1007/s11481-009-9161-7
– volume: 508
  start-page: 134
  year: 2017
  ident: WOS:000404077500015
  article-title: Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis
  publication-title: VIROLOGY
  doi: 10.1016/j.virol.2017.05.013
– volume: 10
  start-page: ARTN 61
  year: 2015
  ident: WOS:000364629200001
  article-title: Glutaminase-containing microvesicles from HIV-1-infected macrophages and immune-activated microglia induce neurotoxicity
  publication-title: MOLECULAR NEURODEGENERATION
  doi: 10.1186/s13024-015-0058-z
– year: 2008
  ident: 000408598500024.58
  article-title: Acyloxyalkyl Carbamate Prodrugs, Methods of Synthesis and Use
  publication-title: WO Pat. Appl.
– volume: 8
  start-page: 594
  year: 2013
  ident: WOS:000320312300014
  article-title: Targeting the Glutamatergic System for the Treatment of HIV-Associated Neurocognitive Disorders
  publication-title: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
  doi: 10.1007/s11481-013-9442-z
– volume: 19
  start-page: 152
  year: 2009
  ident: WOS:000266665400003
  article-title: Cognitive Neuropsychology of HIV-Associated Neurocognitive Disorders
  publication-title: NEUROPSYCHOLOGY REVIEW
  doi: 10.1007/s11065-009-9102-5
– volume: 8
  start-page: 113
  year: 1990
  ident: WOS:A1990CR84100019
  article-title: PHASE-II TRIAL OF 6-DIAZO-5-OXO-L-NORLEUCINE VERSUS ACLACINOMYCIN-A IN ADVANCED SARCOMAS AND MESOTHELIOMAS
  publication-title: INVESTIGATIONAL NEW DRUGS
– volume: 17
  start-page: 3
  year: 2011
  ident: WOS:000289580200002
  article-title: HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors
  publication-title: JOURNAL OF NEUROVIROLOGY
  doi: 10.1007/s13365-010-0006-1
– volume: 205
  start-page: 93
  year: 2000
  ident: WOS:000089711400009
  article-title: Species-dependent and site-specific intestinal metabolism of ester prodrugs
  publication-title: INTERNATIONAL JOURNAL OF PHARMACEUTICS
– volume: 102
  start-page: 3760
  year: 2005
  ident: WOS:000227533100044
  article-title: A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness
  publication-title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  doi: 10.1073/pnas.0500649102
– volume: 8
  start-page: ARTN e76581
  year: 2013
  ident: WOS:000325025200077
  article-title: STAT1 Regulates Human Glutaminase 1 Promoter Activity through Multiple Binding Sites in HIV-1 Infected Macrophages
  publication-title: PLOS ONE
  doi: 10.1371/journal.pone.0076581
– volume: 89
  start-page: 1054
  year: 2000
  ident: WOS:000088733500010
  article-title: In vitro, ex vivo, and in situ intestinal absorption characteristics of the antiviral ester prodrug adefovir dipivoxil
  publication-title: JOURNAL OF PHARMACEUTICAL SCIENCES
– volume: 105
  start-page: 989
  year: 2016
  ident: WOS:000381768500067
  article-title: Interspecies Differences in the Metabolism of a Multiester Prodrug by Carboxylesterases
  publication-title: JOURNAL OF PHARMACEUTICAL SCIENCES
  doi: 10.1002/jps.24632
– volume: 10
  start-page: 1138
  year: 1957
  ident: WOS:A1957WC23400007
  article-title: PHARMACOLOGICAL AND INITIAL THERAPEUTIC OBSERVATIONS ON 6-DIAZO-5-OXO-L-NORLEUCINE (DON) IN HUMAN NEOPLASTIC DISEASE
  publication-title: CANCER
– volume: 109
  start-page: 551
  year: 2009
  ident: WOS:000264345900024
  article-title: In vitro glutaminase regulation and mechanisms of glutamate generation in HIV-1-infected macrophage
  publication-title: JOURNAL OF NEUROCHEMISTRY
  doi: 10.1111/j.1471-4159.2009.05989.x
– volume: 25
  start-page: 625
  year: 2011
  ident: WOS:000287963600011
  article-title: Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment
  publication-title: AIDS
  doi: 10.1097/QAD.0b013e3283427da7
– volume: 7
  start-page: 619
  year: 2012
  ident: WOS:000307556000014
  article-title: Mitochondrial Glutaminase Release Contributes to Glutamate-Mediated Neurotoxicity during Human Immunodeficiency Virus-1 Infection
  publication-title: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
  doi: 10.1007/s11481-012-9364-1
– volume: 73
  start-page: 50
  year: 2014
  ident: WOS:000335647400005
  article-title: Molecular Dissection of the VHL Gene in Solitary Capillary Hemangioblastoma of the Central Nervous System
  publication-title: JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
  doi: 10.1097/NEN.0000000000000024
– volume: 28
  start-page: 1579
  year: 2014
  ident: WOS:000338645000004
  article-title: Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment
  publication-title: AIDS
  doi: 10.1097/QAD.0000000000000303
– volume: 102
  start-page: 539
  year: 2007
  ident: WOS:000247581300023
  article-title: Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase
  publication-title: JOURNAL OF NEUROCHEMISTRY
  doi: 10.1111/j.1471-4159.2007.04594.x
– volume: 95
  start-page: 1177
  year: 2006
  ident: WOS:000237937300002
  article-title: Enzymes involved in the bioconversion of ester-based prodrugs
  publication-title: JOURNAL OF PHARMACEUTICAL SCIENCES
  doi: 10.1002/jps.20542
– volume: 16
  start-page: ARTN 99
  year: 2016
  ident: WOS:000379740400003
  article-title: Case control study: magnetic resonance spectroscopy of brain in HIV infected patients
  publication-title: BMC NEUROLOGY
  doi: 10.1186/s12883-016-0628-x
– volume: 73
  start-page: 443
  year: 2013
  ident: WOS:000314634900010
  article-title: Synaptic Dysfunction in the Hippocampus Accompanies Learning and Memory Deficits in Human Immunodeficiency Virus Type-1 Tat Transgenic Mice
  publication-title: BIOLOGICAL PSYCHIATRY
  doi: 10.1016/j.biopsych.2012.09.026
– volume: 118
  start-page: 359
  year: 2003
  ident: WOS:000182532600007
  article-title: Hippocampal synaptic dysfunction in a murine model of human immunodeficiency virus type 1 encephalitis
  publication-title: NEUROSCIENCE
  doi: 10.1016/S0306-4522(02)00925-9
– year: 2005
  ident: 000408598500024.57
  article-title: Acyloxyalkyl Carbamate Prodrugs, Methods of Synthesis and Use
  publication-title: WO Pat. Appl.
SSID ssj0003123
Score 2.465981
Snippet Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive...
Source Web of Science
SourceID pubmedcentral
proquest
pubmed
webofscience
crossref
acs
SourceType Open Access Repository
Aggregation Database
Index Database
Enrichment Source
Publisher
StartPage 7186
SubjectTerms 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
Title 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
URI http://dx.doi.org/10.1021/acs.jmedchem.7b00966
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000408598500024
https://www.ncbi.nlm.nih.gov/pubmed/28759224
https://www.proquest.com/docview/1925281166
https://pubmed.ncbi.nlm.nih.gov/PMC5795620
Volume 60
WOS 000408598500024
WOSCitedRecordID wos000408598500024
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
journalDatabaseRights – providerCode: PRVABC
  databaseName: American Chemical Society Journals
  customDbUrl:
  eissn: 1520-4804
  dateEnd: 99991231
  omitProxy: false
  ssIdentifier: ssj0003123
  issn: 0022-2623
  databaseCode: ACS
  dateStart: 19630101
  isFulltext: true
  titleUrlDefault: https://pubs.acs.org/action/showPublications?display=journals
  providerName: American Chemical Society
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV3dbtMwFLZgXMANP-Ov_MlI07RKSxc7cRJfVh2jINFVokO7i2zHY926ZGpSie6KV-BReCWehHPSJKUbaOOiitzYrhN_9TmffM5nQjbCRAGT9aQTaimBoAjrSGGgaL1Ac26FdTEb-dMg6B_4Hw_F4ZIoXt7B52xHmbxzgsGKx_asE2r0uYPb5A4PIoZkq9v73Ky8HuNerQ7Owa7XqXL_6AUNkslXDdIVL_PvwZKXDFRpjPYekP06pWcRg3LamRW6Yy6uKjze8DkfkvuVX0q7CyA9Irdsuk7u9urj4NbJ5nAhcj3fpqNlzla-TTfpcCl_PX9Mfg5-ff-xNRwDhLP5BAbYVpNTuDhGTTXGwdMhLNrT2decZkcU_E_6HtCvzsDdpd0UN8lQzJcG0MvuWF1kjnCybxmUJvBJs-nEzjAYgG7t7g_aVOVU0WFWYNATjH9Ux81TcMZp_8MXWuPPJrQUImnipWgtPJo_IQd770a9vlMdDOEo35eF40XCci2tBC4XYCpwAKQUiFwkXBMlLDKu4IkrDfoyJkzcAEqRZoodhRpQY7ynZC3NUvuc0MRwpoyJlGs9PwykFgmPAusJyY0fcd0ibZiYuPpj53G5Z89ZXH5ZzVZczVaLeDWSYlMprONBH5NrWjlNq_OFwsg19d_WII0BAri_o1KbzWBskgseMYZ1ni1A2_QIxBgeifstEq7AuamAMuOrd9LxcSk3LkLg0NxtkY0_gd80RFaAKnkRHq2BP8BuUq1XvR9UXihe_MdLfknucfSsXFjg_VdkrZjO7GvwCwv9plwMfgNJUWWf
linkProvider American Chemical Society
linkToHtml http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV3dbtMwFLbGuBg3_Iy_8mukadqkpcROnDiXU8foYCuV6KbdRbbjsbIuQU0q0V3xCjwKr8STcE6apHSAxi6iyI7t2PGJz3fkcz4TshYmCixZL3JCHUVgoAjrRMJA0nqB5twK62I08kEv6B76747F8RIRdSwMdCKHlvJyE3_OLsBeY95n9Fk8teftUCP0Dm6QmyUZCiKizsdmAfYY92qScA7qvY6Y-0crqJdMvqiX_gCbf_eZvKSnSp20e4ccNaMpXVHO2pNCt83FJaLHaw_3LrldoVS6PROre2TJpqtkpVMfDrdK1vszyuvpFh3MI7jyLbpO-3My7Ol98qP389v3jf4QBDqbjqCfm2p0BjfHqLFGr3jahyV8PPmU0-yEAhqlb-FfUOcAful2iltmSO1LA2hlZ6guMkc42dcMUiO40mw8shN0DaAbOx96m1TlVNF-VqALFPR_UHvRU4DmtLt3RGtptAktaUka7yla05DmD8jh7ptBp-tUx0Q4yvejwvGksFxHNgLLLsDA4ABMVDDrpHCNTJg0ruCJGxlENiZM3ABSUjPFTkItWWi8h2Q5zVL7mNDEcKaMkcq1nh8GkRYJl4H1RMSNL7lukU2YmLj6zfO43MHnLC4zq9mKq9lqEa8WqNhUfOt47MfoilpOU-vLjG_kivKvalmNQQRwt0elNptA3yIuuGQMyzyayW7TIpjJMCTut0i4INVNASQdX3ySDk9L8nERgkXN3RZZ-13-m4poIyBnnsSDNvAF7H-KdarvgzwMxZNrfOSXZKU7ONiP9_d675-SWxwxlwtLv_-MLBfjiX0OiLHQL8r14Rcc8m4K
linkToPdf http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1bb9MwFLZgSMALl3ErVyNN0yYtJXbixHmcWkrHpUSimyZeIsdxWVmXTE0q0T3xF_gp_CV-CeekSbYO0ICHKHJiO3Z87PMd-fg7hKz5iQJL1gksPw4CMFCEsQKhIWkcL-bcCGPjaeR3A6-_677eF_tnQn1BI3KoKS838XFWHyejimGAvcDnn9Fv8cActf0Y4bd3mVwRyAKHqKjzoVmEHcadmiicg4qvT839oRbUTTpf1k2_AM7f-02e01WlXurdJB-bHpXuKIftWRG39ck5ssf_6vItcqNCq3R7IV63ySWTrpJrnTpI3CpZDxfU1_MtOjw9yZVv0XUanpJiz--Q74MfX79thGMQ7Gw-gbZuqskh3CytpjF6x9MQlvLp7FNOsxEFVEpfwZxQRwCC6XaKW2dI8Us9qKU7VieZJazsSwapCVxpNp2YGboI0I3u-8EmVTlVNMwKdIWC9g9rb3oKEJ32d_ZoLZUmoSU9SeNFRWs60vwu2e29HHb6VhUuwlKuGxSWI4XhcWACsPA8PCDsgakK5p0UtpYJk9oWPLEDjQhH-4ntQUrGTLGRH0vma-ceWUmz1DwgNNGcKa2lso3j-l4Qi4RLzzgi4NqVPG6RTRiYqJrueVTu5HMWlQ-r0Yqq0WoRpxaqSFe86xj-Y3JBKaspdbzgHbkg__NaXiMQAdz1UanJZtC2gAsuGcM89xfy29QI5jJ0ibst4i9JdpMByceX36Tjg5KEXPhgWXO7RdbOzoGmINoKyJ0nMeAGfoD9TbZO9X-Qj6F4-A8_-Rm5GnZ70dudwZtH5DpH6GWDBnAfk5ViOjNPADgW8dNyifgJQFJwhA
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=N%E2%80%91%28Pivaloyloxy%29alkoxy-carbonyl+Prodrugs+of+the+Glutamine+Antagonist+6%E2%80%91Diazo-5-oxo%E2%80%91l%E2%80%91norleucine+%28DON%29+as+a+Potential+Treatment+for+HIV+Associated+Neurocognitive+Disorders&rft.jtitle=Journal+of+medicinal+chemistry&rft.au=Nedelcovych%2C+Michael+T&rft.au=Tenora%2C+Luka%CC%81s%CC%8C&rft.au=Kim%2C+Boe-Hyun&rft.au=Kelschenbach%2C+Jennifer&rft.date=2017-08-24&rft.pub=American+Chemical+Society&rft.issn=0022-2623&rft.eissn=1520-4804&rft.volume=60&rft.issue=16&rft.spage=7186&rft.epage=7198&rft_id=info:doi/10.1021%2Facs.jmedchem.7b00966&rft.externalDocID=a091375605
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0022-2623&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0022-2623&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0022-2623&client=summon