Delving into the Latest Updates on GW-274150 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

NOS2

Mechanism

NOS2 inhibitors(Nitric oxide synthase, inducible inhibitors)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesSkin and Musculoskeletal Diseases+ [1]

Active Indication-

Inactive Indication

Acute migraineAsthmaHeadache+ [2]

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC8H17N3O2S

InChIKeyMOLOJNHYNHBPCW-ZETCQYMHSA-N

CAS Registry210354-22-6

Nitric oxide (NO) is likely to be involved in the development of migraine headache. Nitric oxide synthase (NOS) is an important chemical involved in the production of NO. Reduction of NOS, and therefore NO, may be an effective technique for the treatment of migraine headache. GW274150 is a highly selective inhibitor of NOS and offers the potential of anti-inflammatory activity in migraine through a novel mechanism of action. The intent of this study is to investigate the safety and efficacy of GW274150 for the acute treatment of migraine headache.

Start Date01 Dec 2005

Sponsor / Collaborator

GSK Plc

NCT00242866 / CompletedPhase 2

A Multicentre, Two-part, Randomised, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy, Tolerability and Pharmacokinetics of the iNOS Inhibitor GW274150 Administered up to 120mg Daily for 12 Weeks in the Prophylactic Treatment of Migraine.

Nitric oxide (NO) is likely to be involved in the development of migraine headache. Nitric oxide synthase (NOS) is an important chemical involved in the production of NO. Reduction of NOS, and therefore NO, may be an effective technique for the prevention of migraine headache. GW274150 is a highly selective inhibitor of NOS and offers the potential of anti-inflammatory activity in migraine through a novel mechanism of action. The intent of this study is to investigate the safety and efficacy of GW274150 for the prophylactic treatment of migraine headache.

Start Date01 Oct 2005

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with GW-274150

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100 Translational Medicine associated with GW-274150

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100 Patents (Medical) associated with GW-274150

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29

Literatures (Medical) associated with GW-274150

07 Jul 2021·EMBO Molecular MedicineQ1 · MEDICINE

Pharmacological or genetic inhibition of iNOS prevents cachexia‐mediated muscle wasting and its associated metabolism defects

Q1 · MEDICINE

ArticleOA

Author: Sanguin‐Gendreau, Virginie ; Bianchi, Marco Emilio ; Hall, Derek T ; Sadek, Jason ; Muller, William ; Di Marco, Sergio ; Gallouzi, Imed‐Eddine ; Colalillo, Bianca ; Tremblay, Anne‐Marie K ; Omer, Amr

Cachexia syndrome develops in patients with diseases such as cancer and sepsis and is characterized by progressive muscle wasting. While iNOS is one of the main effectors of cachexia, its mechanism of action and whether it could be targeted for therapy remains unexplored. Here, we show that iNOS knockout mice and mice treated with the clinically tested iNOS inhibitor GW274150 are protected against muscle wasting in models of both septic and cancer cachexia. We demonstrate that iNOS triggers muscle wasting by disrupting mitochondrial content, morphology, and energy production processes such as the TCA cycle and acylcarnitine transport. Notably, iNOS inhibits oxidative phosphorylation through impairment of complexes II and IV of the electron transport chain and reduces ATP production, leading to energetic stress, activation of AMPK, suppression of mTOR, and, ultimately, muscle atrophy. Importantly, all these effects were reversed by GW274150. Therefore, our data establish how iNOS induces muscle wasting under cachectic conditions and provide a proof of principle for the repurposing of iNOS inhibitors, such as GW274150 for the treatment of cachexia.

01 Jan 2017·Nitric OxideQ2 · BIOLOGY

Nitric oxide-mediated resistance to photodynamic therapy in a human breast tumor xenograft model: Improved outcome with NOS2 inhibitors

Q2 · BIOLOGY

Article

Author: Fahey, Jonathan M ; Girotti, Albert W

Many malignant tumors employ iNOS-derived NO to resist eradication by chemotherapeutic agents or ionizing radiation. In this study, we determined whether human breast carcinoma MDA-MB-231 cells in vitro and in vivo as tumor xenografts would exploit endogenous iNOS/NO to resist the cytotoxic effects of 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT). Broad band visible irradiation of ALA-treated cells resulted in a marked after-light upregulation of iNOS protein which persisted for at least 24 h. Apoptotic killing of ALA/light-challenged cells was significantly enhanced by iNOS inhibitors (1400W, GW274150) and a NO trap (cPTIO), implying that stress-induced iNOS/NO was acting cytoprotectively. We found that cells surviving the photostress proliferated and migrated more rapidly than controls in 1400W- and cPTIO-inhibitable fashion, indicating iNOS/NO involvement. Female SCID mice bearing MDA-MB-231 tumors were used for animal model experiments. ALA-PDT with a 633 nm light source caused a significant reduction in post-irradiation tumor growth relative to light-only controls, which was further reduced by administration of 1400W or GW274150, whereas 1400W had little or no effect on controls. Immunoblot analyses of tumor samples revealed a progressive post-PDT upregulation of iNOS, which reached >5-times the control level after six days. Correspondingly, the nitrite/nitrate level in post-PDT tumor samples was substantially higher than that in controls. In addition, a 1400W-inhibitable upregulation of pro-survival/progression effector proteins such as Bcl-xL, Survivin, and S100A4 was observed after in vitro and in vivo ALA-PDT. This is the first known study to demonstrate iNOS/NO-induced resistance to PDT in an in vivo human tumor model.

01 Nov 2014·Molecular and Biochemical ParasitologyQ4 · MEDICINE

Plasmodium falciparum avoids change in erythrocytic surface expression of phagocytosis markers during inhibition of nitric oxide synthase activity

Q4 · MEDICINE

Article

Author: Maretty, Lasse ; Jensen, Peter Ø ; Hempel, Casper ; Kohnke, Hannes ; Kurtzhals, Jørgen A L ; Staalsø, Trine

Nitric oxide (NO) accumulates in Plasmodium falciparum-infected erythrocytes. It may be produced by a parasite NO synthase (NOS) or by nitrate reduction. The parasite's benefit of NO accumulation is not understood. We investigated if inhibiting the P. falciparum NOS with specific and unspecific NOS inhibitors led to a decrease in intraerythrocytic NO accumulation and if this was associated with a change in surface expression of the phagocytosis markers CD47 and phosphatidyl serine. The specific inducible NOS inhibitors l-canavanine and GW274150 dose-dependently decreased intraerythrocytic NO while l-NMMA (an unspecific NOS inhibitor) and caveolin-1 scaffolding domain peptide (a specific endothelial NOS inhibitor) did not affect NO levels. Phosphatidyl serine externalization markedly increased upon P. falciparum infection. l-canavanine did not modify this whereas caveolin-1 scaffolding domain peptide increased the fraction of phosphatidyl serine exposing cells significantly. The infection did not change the level of expression of neither total CD47 nor its oxidized form. Unrelated to NOS inhibition, incubation with caveolin-1 scaffolding domain peptide lead to a decrease in oxidized CD47. In conclusion, the data imply that NOS inhibitors decrease NO accumulation in P. falciparum-infected erythrocytes but this does not correlate with the level of two major erythrocytic phagocytosis markers.

100 Deals associated with GW-274150

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12237

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Migraine Disorders	Phase 2	DK	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	ES	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	DE	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	NL	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	IT	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	BE	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	FR	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	FI	GSK Plc	01 Oct 2005
Migraine Disorders	Phase 2	NO	GSK Plc	01 Oct 2005
Rheumatoid Arthritis	Phase 2	GB	GSK Plc	01 Aug 2005