Delving into the Latest Updates on N-6022 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GSNOR

Mechanism

GSNOR inhibitors(S-nitrosoglutathione reductase inhibitors)

Therapeutic Areas

NeoplasmsNervous System Diseases

Active Indication

Brain Cancer

Inactive Indication

AsthmaCystic FibrosisInflammatory Bowel Diseases+ [1]

Originator Organization

Nivalis Therapeutics, Inc.

Active Organization

Texas Tech University Health Sciences Center

Inactive Organization

Nivalis Therapeutics, Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC24H22N4O3

InChIKeyYVPGZQLRPAGKLA-UHFFFAOYSA-N

CAS Registry1208315-24-5

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.

Start Date01 Apr 2011

Sponsor / Collaborator

Nivalis Therapeutics, Inc.

NCT01147406 / CompletedPhase 1

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.

Start Date01 Aug 2010

Sponsor / Collaborator

Nivalis Therapeutics, Inc.

100 Clinical Results associated with N-6022

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100 Translational Medicine associated with N-6022

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100 Patents (Medical) associated with N-6022

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25

Literatures (Medical) associated with N-6022

01 Jun 2024·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

Author: 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.

01 Mar 2024·Free Radical Biology and Medicine

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

Article

Author: 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.

01 Jan 2024·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

Author: 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 Deals associated with N-6022

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 1	US	Nivalis Therapeutics, Inc.	01 Feb 2014
Asthma	Phase 1	US	Nivalis Therapeutics, Inc.	01 Mar 2011
Inflammatory Bowel Diseases	Phase 1	US	Nivalis Therapeutics, Inc.	-
Pulmonary Disease, Chronic Obstructive	Phase 1	US	Nivalis Therapeutics, Inc.	-
Brain Cancer	Preclinical	US	Texas Tech University Health Sciences Center	01 Jul 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01746784 (SNO-1, CTgov)	Phase 1	Cystic Fibrosis	66	normal saline	cbdyhyqcuq(uohivufgil) = rhsbexughy errbripfdl (ajrbuwldpv, egdffrlgdl - nggnpglhkb) View more	-	24 Nov 2014
NCT01147406 (CTgov)	Phase 1	-	41	Placebo	xelfmoeykj(bjvjmqylwq) = bpfsitndce hslevvzaqp (litewmixcw, patvaxwrqs - suvewieptt) View more	-	07 Mar 2014