更新于：2024-11-21

AR-C133057XX

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

Inducible NOS inhibitors(AstraZeneca)

靶点

NOS2

作用机制

NOS2抑制剂(诱导型一氧化氮合酶抑制剂)

治疗领域-

在研适应症-

非在研适应症-

原研机构

AstraZeneca R&D Charnwood

在研机构

AstraZeneca R&D Charnwood

非在研机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C19H20N4O2

InChIKeySZUVGMCKKLJAFX-UHFFFAOYSA-N

CAS号268730-08-1

关联

100 项与 AR-C133057XX 相关的临床结果

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100 项与 AR-C133057XX 相关的转化医学

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100 项与 AR-C133057XX 相关的专利（医药）

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103

项与 AR-C133057XX 相关的文献（医药）

2024-09-01·Cephalalgia

Mechanisms of GTN-induced migraine: Role of NOS isoforms, sGC and peroxynitrite in a migraine relevant mouse model

Article

作者: Olesen, Jes ; Christensen, Sarah Louise ; Guo, Song ; Obelitz-Ryom, Karina ; Ernstsen, Charlotte ; Kristensen, David Møbjerg B.

Background Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon. Methods Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312). Results Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase. Conclusions Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.

2024-08-01·Archives of Biochemistry and Biophysics

New advances in the protective mechanisms of acidic pH after ischemia: Participation of NO

Article

作者: Ennis, Irene Lucía ; Vila Petroff, Martín Gerardo ; Fantinelli, Juliana Catalina ; Mosca, Susana María ; Ciocci Pardo, Alejandro ; Godoy Coto, Joshua ; González Arbeláez, Luisa Fernanda ; Burgos, Juan Ignacio

BACKGROUNDIt has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death.OBJECTIVETo examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model.METHODSIsolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca²⁺ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis.RESULTSAR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR.CONCLUSIONSOur data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.

2024-01-01·The Journal of Nutritional Biochemistry

Antibiotics attenuate diet-induced nonalcoholic fatty liver disease without altering intestinal barrier dysfunction

Article

作者: Halilbasic, Emina ; Trauner, Michael ; Staltner, Raphaela ; Brandt, Annette ; Camarinha-Silva, Amélia ; Baumann, Anja ; Bergheim, Ina ; Csarmann, Katja ; Hernández-Arriaga, Angélica

To date the role of the alterations of intestinal microbiota in the development of intestinal barrier dysfunction in settings of nonalcoholic fatty liver disease (NAFLD) has not been fully understood. Here, we assessed the effect of antibiotics on development of NAFLD and their impact on intestinal barrier dysfunction. Male C57BL/6J mice were either pair-fed a liquid control diet (C) or fat- and fructose-rich diet (FFr) +/- antibiotics (AB, ampicillin/vancomycin/metronidazole/gentamycin) for 7 weeks. Fasting blood glucose was determined and markers of liver damage, inflammation, intestinal barrier function, and microbiota composition were assessed. The development of hepatic steatosis with early signs of inflammation found in FFr-fed mice was significantly abolished in FFr+AB-fed mice. Also, while prevalence of bacteria in feces was not detectable and TLR4 ligand levels in portal plasma were at the level of controls in FFr+AB-fed mice, impairments of intestinal barrier function like an increased permeation of xylose and iNOS protein levels persisted to a similar extent in both FFr-fed groups irrespective of AB use. Exposure of everted small intestinal tissue sacs of naïve mice to fructose resulted in a significant increase in tissue permeability and loss of tight junction proteins, being not affected by the presence of AB, whereas the concomitant treatment of tissue sacs with the NOS inhibitor aminoguanidine attenuated these alterations. Taken together, our data suggest that intestinal barrier dysfunction in diet-induced NAFLD in mice may not be predominantly dependent on changes in intestinal microbiota but rather that fructose-induced alterations of intestinal NO-homeostasis might be critically involved.

100 项与 AR-C133057XX 相关的药物交易

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