Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver
Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver
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DOI：
10.1021/jm9701031
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发表时间：
1997-06-20
影响因子：
7.3
通讯作者：
Keefer, LK
中科院分区：
文献类型：
--
作者：
Saavedra, JE;Billiar, TR;Keefer, LK
我们设计了一种药物，通过器官选择性药理学产生的生物调节剂一氧化氮（NO），保护肝脏免于凋亡细胞死亡。发现策略包括三个步骤：鉴定二醇二氮烯鎓离子（R2 N [N（O）NO]（-），其中R2 N =吡咯烷基），其在生理pH下自发分解为具有非常短的半衰期（3 s）的NO;通过共价连接保护基团将该离子转化为一系列潜在的前药衍生物，我们假设这些保护基团可能被肝脏中普遍存在的酶快速去除;以及在体外和体内筛选前药候选物以选择先导物并确认所需的活性。在检测的五种细胞类型中，只有培养的肝细胞将O-2-乙烯基1-（吡咯烷-1-基）二氮烯-1-鎓-1，2-二醇盐（V-PYRRO/NO）代谢为NO，触发环鸟苷3 '，5'-单磷酸（cGMP）合成，并保护肝细胞免受肿瘤坏死因子-α（TNF α）加放线菌素D处理诱导的细胞凋亡。在体内，V-PYRRO/NO增加肝脏cGMP水平，同时最小限度地影响全身血液动力学，保护给予TNF α加半乳糖胺的大鼠免于细胞凋亡和肝毒性。结果说明了二醇二氮烯鎓在体内靶向NO递送的潜在效用，并提出了一种可能的治疗肝脏疾病如暴发性肝功能衰竭的策略。
We have designed a drug that protects the liver from apoptotic cell death by organ-selective pharmacological generation of the bioregulatory agent, nitric oxide (NO). The discovery strategy involved three steps: identifying a diazeniumdiolate ion (R2N[N(O)NO](-), where R2N = pyrrolidinyl) that spontaneously decomposes to NO with a very short half-life (3 s) at physiological pH; converting this ion to a series of potential prodrug derivatives by covalent attachment of protecting groups that we postulated might be rapidly removed by enzymes prevalent in the liver; and screening the prodrug candidates in vitro and in vivo to select a lead and to confirm the desired activity. Of five cell types examined, only cultured hepatocytes metabolized O-2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) to NO, triggering cyclic guanosine 3',5'-monophosphate (cGMP) synthesis and protecting the hepatocytes from apoptotic cell death induced by treatment with tumor necrosis factor-alpha (TNF alpha) plus actinomycin D. In vivo, V-PYRRO/NO increased Liver cGMP levels while minimally affecting systemic hemodynamics, protecting rats dosed with TNF alpha plus galactosamine from apoptosis and hepatotoxicity. The results illustrate the potential utility of diazeniumdiolates for targeting NO delivery in vivo and suggest a possible therapeutic strategy for hepatic disorders such as fulminant liver failure.