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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25

项与 N-6022 相关的文献（医药）

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 ; Zhang, Bao-Gang ; Ma, Chang-Sheng ; 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.

2024-01-01·Life Sciences

Mechanistic study of the Aldo-keto reductase family 1 member A1 in regulating mesenchymal stem cell fate decision toward adipogenesis and osteogenesis

Article

作者: Kao, Yu-Cuieh ; Weng, Shuo-Chun ; Lin, Yi-Hui ; Liou, Ying-Ming ; Chen, Chuan-Mu ; Chiang, Chen Hao

AIMSAkr1A1 is a glycolytic enzyme catalyzing the reduction of aldehyde to alcohol. This study aims to delineate the role of Akr1A1 in regulating the adipo-osteogenic lineage differentiation of mesenchymal stem cells (MSCs).MAIN METHODSMSCs derived from human bone marrow and Wharton Jelly together with gain- and loss-of-function analysis as well as supplementation with the S-Nitrosoglutathione reductase (GSNOR) inhibitor N6022 were used to study the function of Akr1A1 in controlling MSC lineage differentiation into osteoblasts and adipocytes.KEY FINDINGSAkr1A1 expression, PKM2 activity, and lactate production were found to be decreased in osteoblast-committed MSCs, but PGC-1α increased to induce mitochondrial oxidative phosphorylation. Increased Akr1A1 inhibited the SIRT1-dependent pathway for decreasing the expressions of PGC-1α and TAZ but increasing PPAR γ in adipocyte-committed MSCs, hence promoting glycolysis in adipogenesis. In contrast, Akr1A1 expression, PKM2 activity and lactate production were all increased in adipocyte-differentiated cells with decreased PGC-1α for switching energy utilization to glycolytic metabolism. Reduced Akr1A1 expression in osteoblast-committed cells relieves its inhibition of SIRT1-mediated activation of PGC-1α and TAZ for facilitating osteogenesis and mitochondrial metabolism.SIGNIFICANCESeveral metabolism-involved regulators including Akr1A1, SIRT1, PPARγ, PGC-1α and TAZ were differentially expressed in osteoblast- and adipocyte-committed MSCs. More importantly, Akr1A1 was identified as a new key regulator for controlling the MSC lineage commitment in favor of adipogenesis but detrimental to osteogenesis. Such information should be useful to develop perspective new therapeutic agents to reverse the adipo-osteogenic differentiation of BMSCs, in a way to increase in osteogenesis but decrease in adipogenesis.

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
囊性纤维化	临床1期	美国	Nivalis Therapeutics, Inc.	2014-02-01
哮喘	临床1期	美国	Nivalis Therapeutics, Inc.	2011-03-01
炎症性肠病	临床1期	美国	Nivalis Therapeutics, Inc.	-
慢性阻塞性肺疾病	临床1期	美国	Nivalis Therapeutics, Inc.	-
脑癌	临床前	美国	Texas Tech University Health Sciences Center	2017-07-01

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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	簾憲齋構壓窪製餘廠選(膚獵構醖鬱製襯構艱糧) = 網艱鑰鹹窪鏇廠簾窪艱膚憲夢積簾餘襯繭夢製 (鬱製憲鏇遞觸築鏇製製, 觸艱憲膚鹽衊簾繭築鬱 ~ 鬱簾壓選醖願積膚蓋顧) 更多	-	2014-11-24
NCT01147406 (CTgov)	临床1期	-	41	Placebo	鹹鬱鹹廠簾鏇顧獵襯鹹(範觸鬱襯糧願願範選衊) = 願衊憲憲蓋夢築選製顧繭築構構築蓋獵艱艱繭 (遞獵觸艱選鏇積繭積選, 選獵積構範淵簾醖築範 ~ 繭觸醖鏇製鑰觸簾糧鏇) 更多	-	2014-03-07