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.
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DOI：
10.1021/acs.jmedchem.7b00966
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发表时间：
2017-08-24
影响因子：
7.3
通讯作者：
Slusher BS
中科院分区：
文献类型：
--
作者：
Nedelcovych MT;Tenora L;Kim BH;Kelschenbach J;Chao W;Hadas E;Jančařík A;Prchalová E;Zimmermann SC;Dash RP;Gadiano AJ;Garrett C;Furtmüller G;Oh B;Brandacher G;Alt J;Majer P;Volsky DJ;Rais R;Slusher BS
异常兴奋性神经传递与谷氨酸过度产生有关，与hiv相关的神经认知障碍（HAND）的发展有关。谷氨酰胺拮抗剂6-重氮-5-氧- l -去甲亮氨酸（DON, 14）减弱hiv感染的小胶质细胞/巨噬细胞中的谷氨酸合成，为HAND的治疗提供了潜力。我们发现，14可以防止嵌合ecohiv感染小鼠（HAND模型）出现空间记忆缺陷。然而，由于其发展受到外周毒性的阻碍，目前尚无临床可用的14。我们描述了几种取代的N-（戊酰氧基）烷氧羰基14的前药的合成，这些前药被设计成在血浆中惰性循环，并被吸收并在大脑中生物转化为14。前药先导异丙基6-重氮-5-氧-2-（（苯基（戊氧基）甲氧基）羰基）氨基己酸酯（13d）在猪和人血浆中稳定，但在猪脑匀浆中释放。当猪全身给药时，13d提供了15倍的csf -血浆比和9倍的脑-血浆比（相对于14），为HAND的治疗开辟了可能的临床途径。
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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影响因子：
3.2
作者：
Heaton, Robert K.;Franklin, Donald R.;Ellis, Ronald J.;McCutchan, J. Allen;Letendre, Scott L.;LeBlanc, Shannon;Corkran, Stephanie H.;Duarte, Nichole A.;Clifford, David B.;Woods, Steven P.;Collier, Ann C.;Marra, Christina M.;Morgello, Susan;Mindt, Monica Rivera;Taylor, Michael J.;Marcotte, Thomas D.;Atkinson, J. Hampton;Wolfson, Tanya;Gelman, Benjamin B.;McArthur, Justin C.;Simpson, David M.;Abramson, Ian;Gamst, Anthony;Fennema-Notestine, Christine;Jernigan, Terry L.;Wong, Joseph;Grant, Igor
通讯作者：
Grant, Igor
DOI：
10.1097/nen.0000000000000026
发表时间：
2014-01-01
影响因子：
3.2
作者：
He, Hongxia;Sharer, Leroy R.;Volsky, David J.
通讯作者：
Volsky, David J.
DOI：
10.1098/rspb.1984.0028
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CHUNG, SH;JOHNSON, MS
通讯作者：
JOHNSON, MS
影响因子：
2.6
作者：
Doi, Akihiro;Iijima, Kenta;Ishizaka, Yukihito
通讯作者：
Ishizaka, Yukihito
影响因子：
10.6
作者：
Fitting, Sylvia;Ignatowska-Jankowska, Bogna M.;Bull, Cecilia;Skoff, Robert P.;Lichtman, Aron H.;Wise, Laura E.;Fox, Michael A.;Su, Jianmin;Medina, Alexandre E.;Krahe, Thomas E.;Knapp, Pamela E.;Guido, William;Hauser, Kurt F.
通讯作者：
Hauser, Kurt F.