N-6022(N-6022) - 药物靶点：GSNOR_在研适应症：脑癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

GSNOR

作用机制

GSNOR抑制剂(GSNOR抑制剂)

治疗领域

肿瘤神经系统疾病

在研适应症

脑癌

非在研适应症

哮喘囊性纤维化炎症性肠病+ [1]

原研机构

Nivalis Therapeutics, Inc.

在研机构

Texas Tech University Health Sciences Center

非在研机构

Nivalis Therapeutics, Inc.

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C24H22N4O3

InChIKeyYVPGZQLRPAGKLA-UHFFFAOYSA-N

CAS号1208315-24-5

关联

3

项与 N-6022 相关的临床试验

NCT01746784 / Completed临床1期

A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study of N6022 to Evaluate Safety and Pharmacokinetics in Subjects With Cystic Fibrosis Homozygous for the F508del-CFTR Mutation (SNO1)

The purpose of this study is to investigate the safety, tolerability and pharmacokinetics of N6022, and to obtain descriptive information on the effect of N6022 on biomarkers of CFTR function and inflammation in adult cystic fibrosis subjects who are homozygous for the F508del-CFTR mutation.

开始日期2014-02-01

申办/合作机构

Nivalis Therapeutics, Inc.

NCT01339897 / Completed临床1期

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of N6022 in Healthy Subjects

This Phase 1 study will evaluate multiple doses across a range that has been found to be effective in mouse models of asthma and safe in one Phase 1 clinical trial. It is intended to provide evidence of the tolerability of multiple doses as well as provide information on the Pharmacokinetic (PK) and metabolism of N6022 in humans.

开始日期2011-04-01

申办/合作机构

Nivalis Therapeutics, Inc.

NCT01147406 / Completed临床1期

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effect of N6022 in Healthy Subjects

The purpose of this study is to evaluate the safety and tolerability of N6022 in healthy subjects.

开始日期2010-08-01

申办/合作机构

Nivalis Therapeutics, Inc.

100 项与 N-6022 相关的临床结果

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100 项与 N-6022 相关的转化医学

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100 项与 N-6022 相关的专利（医药）

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26

项与 N-6022 相关的文献（医药）

2024-11-01·Neuroscience

The role of S-nitrosoglutathione reductase (GSNOR) in T cell-mediated immunopathology of experimental autoimmune encephalomyelitis (EAE)

Article

作者: Kim, Judong ; Touhidul Islam, S.M. ; Singh, Avtar K ; Singh, Inderjit ; Touhidul Islam, S M ; Fei, Qiao ; Won, Jeseong

Previously, we reported that both S-nitrosoglutathione (GSNO), a carrier of cellular nitric oxide, and N6022, an injectable form of GSNO reductase (GSNOR) inhibitor that increases endogenous GSNO levels, alleviate experimental autoimmune encephalomyelitis (EAE) in mice by suppressing Th1 and Th17 immune responses. Building on these findings, we explored the role of GSNOR in EAE pathogenesis and evaluated the efficacy of an orally active GSNOR inhibitor (N91115) in treating the EAE disease. EAE mice exhibited heightened expression/activity of GSNOR in the spinal cord, and the knockout of the GSNOR gene resulted in much milder clinical manifestations of EAE, with lower degrees of demyelination and axonal loss, reduced microglial and astrocyte activations, as well as suppressed Th1 and Th17 cell responses, alongside bolstered Treg immune responses. Next, we evaluated the efficacy of N91115 against EAE immunopathology. Consistent with our findings in GSNOR deficient EAE mice, daily N91115 administration reduced clinical EAE severity, with less spinal cord demyelination and axonal loss compared to untreated EAE mice. Furthermore, N91115 treated EAE mice showed diminished Th1 and Th17 immune responses and enhanced Treg responses. This observation underscores the potential of increased GSNOR expression and activity as a risk factor exacerbating EAE immunopathology, while simultaneously highlighting its potential as a target for modifying the disease. Furthermore, the balanced immune regulation provided by orally active N91115 (IL-6/IL-17a vs. IL-10) presents a promising alternative to immunosuppressive drugs, reducing the risk of opportunistic infections.

2024-06-01·European Journal of Pharmacology

N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis

Article

作者: Han, Bo ; Ma, Ya-Ping ; Li, P Andy ; He, Mao-Tao ; Dong, Hao ; Duan, Wan-Li ; Ma, Chang-Sheng ; Zhang, Bao-Gang ; Wang, Xue-Jie ; Sheng, Zhi-Mei ; Zhang, Li-Ying

Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a "first-in-class" drug for asthma with potential therapeutic applications. However, it remains unclear whether N6022 exerts protective effects in ischemic stroke, and the precise mechanisms of its action are unknown. This study aimed to investigate whether N6022 mitigates cerebral ischemia/reperfusion (I/R) injury by reducing ferroptosis and to elucidate the underlying mechanisms. Accordingly, we established an oxygen-glucose deprivation/reperfusion (OGD/R) cell model and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to mimic cerebral I/R injury. Our data, both in vitro and in vivo, demonstrated that N6022 effectively protected against I/R-induced brain damage and neurological deficits in mice, as well as OGD/R-induced BV2 cell damage. Mechanistically, N6022 promoted Nrf2 nuclear translocation, enhancing intracellular antioxidant capacity of SLC7A11-GPX4 system. Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis.

2024-03-01·Free Radical Biology and Medicine

Sterile inflammation induces vasculopathy and chronic lung injury in murine sickle cell disease

Article

作者: Teng, Ru-Jeng ; Xu, Hao ; Hillery, Cheryl A ; Garcia, Guilherme ; Jones, Deron W ; Pritchard, Kirkwood A ; Jing, Xigang ; Hogg, Neil ; Rarick, Kevin R ; Day, Billy W ; Naylor, Stephen ; Li, Keguo ; Martin, Dustin P

Murine sickle cell disease (SCD) results in damage to multiple organs, likely mediated first by vasculopathy. While the mechanisms inducing vascular damage remain to be determined, nitric oxide bioavailability and sterile inflammation are both considered to play major roles in vasculopathy. Here, we investigate the effects of high mobility group box-1 (HMGB1), a pro-inflammatory damage-associated molecular pattern (DAMP) molecule on endothelial-dependent vasodilation and lung morphometrics, a structural index of damage in sickle (SS) mice. SS mice were treated with either phosphate-buffered saline (PBS), hE-HMGB1-BP, an hE dual-domain peptide that binds and removes HMGB1 from the circulation via the liver, 1-[4-(aminocarbonyl)-2-methylphenyl]-5-[4-(1H-imidazol-1-yl)phenyl]-1H-pyrrole-2-propanoic acid (N6022) or N-acetyl-lysyltyrosylcysteine amide (KYC) for three weeks. Human umbilical vein endothelial cells (HUVEC) were treated with recombinant HMGB1 (r-HMGB1), which increases S-nitrosoglutathione reductase (GSNOR) expression by ∼80%, demonstrating a direct effect of HMGB1 to increase GSNOR. Treatment of SS mice with hE-HMGB1-BP reduced plasma HMGB1 in SS mice to control levels and reduced GSNOR expression in facialis arteries isolated from SS mice by ∼20%. These changes were associated with improved endothelial-dependent vasodilation. Treatment of SS mice with N6022 also improved vasodilation in SS mice suggesting that targeting GSNOR also improves vasodilation. SCD decreased protein nitrosothiols (SNOs) and radial alveolar counts (RAC) and increased GSNOR expression and mean linear intercepts (MLI) in lungs from SS mice. The marked changes in pulmonary morphometrics and GSNOR expression throughout the lung parenchyma in SS mice were improved by treating with either hE-HMGB1-BP or KYC. These data demonstrate that murine SCD induces vasculopathy and chronic lung disease by an HMGB1- and GSNOR-dependent mechanism and suggest that HMGB1 and GSNOR might be effective therapeutic targets for reducing vasculopathy and chronic lung disease in humans with SCD.

100 项与 N-6022 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12206

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脑癌	临床前	美国	Texas Tech University Health Sciences Center	2017-07-01
囊性纤维化	药物发现	美国	Nivalis Therapeutics, Inc.	2014-02-01
哮喘	药物发现	美国	Nivalis Therapeutics, Inc.	2011-03-01
炎症性肠病	药物发现	美国	Nivalis Therapeutics, Inc.	-
慢性阻塞性肺疾病	药物发现	美国	Nivalis Therapeutics, Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01746784 (SNO-1, CTgov)	临床1期	囊性纤维化	66	normal saline	獵顧廠衊糧獵窪獵鬱鬱(製簾遞襯築積壓艱獵鏇) = 簾繭廠構鏇夢鏇憲齋膚壓鹹壓壓範鹽繭顧簾蓋 (積窪構願醖壓構選網醖, 鹽衊觸鬱齋鏇築簾願夢 ~ 窪製夢網齋願簾簾鬱醖) 更多	-	2014-11-24
NCT01147406 (CTgov)	临床1期	-	41	Placebo	鏇願蓋鑰蓋獵鹽糧蓋鑰(顧鹹糧鬱膚淵製鹽顧廠) = 遞積鑰齋廠餘餘艱齋簾壓顧鹹蓋遞醖鏇製遞積 (鏇衊積齋顧遞築衊壓淵, 糧構構積齋鬱醖構蓋遞 ~ 艱衊簾遞鑰網鑰憲醖衊) 更多	-	2014-03-07