Delving into the Latest Updates on GSK-2256294 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

2256294, GSK 2256294

Target

EPHX2

Mechanism

EPHX2 inhibitors(Epoxide hydratase inhibitors)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus

Inactive Indication

ObesityPulmonary Disease, Chronic Obstructive

Originator Organization

GSK Plc

Active Organization

GSK Plc

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC21H24F3N7O

InChIKeyLQHDJQIMETZMPH-ZBFHGGJFSA-N

CAS Registry1142090-23-0

Soluble epoxide hydrolase (sEH) is the metabolizing enzyme of epoxyeicosatrienoic acids (EETs), which may play a role in reducing neuroinflammation and regulating cerebral blood flow after subarachnoid hemorrhage (SAH). Hypotheses: Pharmacologic inhibition of the sEH enzyme is safe and will result in increased EETs availability in the blood and cerebrospinal fluid. This study is a double-blind, placebo-controlled, phase 1b randomized trial to evaluate the safety and efficacy of GSK2256294, a novel soluble epoxide hydrolase inhibitor in patients with aneurysmal SAH.

Start Date02 May 2018

Sponsor / Collaborator

Oregon Health & Science University

[+2]

NCT02262689 / CompletedPhase 1

A Randomised Placebo-controlled Study to Evaluate the Effects of GSK2256294 Following Repeat Dosing on Pulmonary Artery Pressure in Healthy Volunteers Under Normoxic and Hypoxic Conditions

The study evaluates the effect of GSK2256294 exposure at steady state on pulmonary artery systolic pressure (PASP) in healthy volunteers, under hypoxic conditions, after 7 days of dosing. It is single centre, double blind, randomized, placebo-controlled study to be conducted in approximately 30 healthy volunteers. Subjects will be screened no more than 30 days. Subject will be admitted in clinical unit on Day -1. Subject will be dosed for 7 days in unit in morning on all days except for dosing on Days 3 -6. Dosing on Days 3 -6 will occur at home. Subjects will return to the unit on the evening of Day 6 and remain there until Day 8. Subjects will undergo echocardiography under normoxic and hypoxic on Day 1 pre-dose and on Day 7 post-dose. Subject will be followed up for 28- 32 days after discharge. The maximum estimated time that a subject will be enrolled in the study is 62 days from the screening visit to follow up.

Start Date08 Jan 2015

Sponsor / Collaborator

GSK Plc

[+1]

100 Clinical Results associated with GSK-2256294

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100 Translational Medicine associated with GSK-2256294

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100 Patents (Medical) associated with GSK-2256294

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9

Literatures (Medical) associated with GSK-2256294

01 Jan 2023·American journal of translational research

Soluble epoxide hydrolase inhibitors for smoking-associated inflammatory lung diseases and chronic obstructive pulmonary disease: a meta-analytical systematic review of preclinical and clinical studies.

Review

Author: Miguel, Camila B ; Martins-de-Abreu, Melissa C ; Trindade-da-Silva, Carlos A ; Felipe, Alberto G Borges ; Perissinotto, Rodrigo ; Oliveira, Carlo J Freire ; Miguel-Neto, Jamil ; Bernardes, Ana P Lazarin ; Rodrigues, Wellington F

An evaluation of the inflammatory enzymatic interactions related to pulmonary function can help identify biomarkers for interventions or prophylactic measures to improve patient prognosis. This study aimed to determine the effect of epoxide hydrolase inhibition by GSK2256294 in different pulmonary inflammation models. A secondary search was performed using Medline/PubMed, Web of Science, SciELO, Cochrane Library, Embase, Academic Google, and gray literature by two independent reviewers, who analyzed the methodological quality and consistency of the data. Different variables were compared using a meta-analysis. A total of 86 studies were found, 4 of which were selected from the gray literature. Based on the eligibility criteria, two clinical and one preclinical studies were evaluated. GSK2256294 inhibited the soluble epoxide hydrolase enzyme in both clinical and preclinical models, exhibiting greater effectiveness in clinical studies and contributing to the anti-inflammatory activity mediated by the eicosatrienoic pathway by reducing the levels of dihydroxyeicosatrienoic acids and leukotoxin-diol. Overall, GSK2256294 was identified as a promising drug for controlling the deleterious manifestations of lung inflammation. Further clinical and preclinical studies are required to ensure consistency among the evidence and identify other biological activities mediated by GSK2256294.

01 Jun 2022·Neurocritical careQ3 · MEDICINE

A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage

Q3 · MEDICINE

Article

Author: Martini, Ross P ; Cetas, Justin ; Siler, Dominic ; Treggiari, Miriam M ; Allen, Elyse ; Alkayed, Nabil J

BACKGROUND:

Epoxyeicosatrienoates (EETs) are endogenous regulators of neuroinflammation and cerebral blood flow. Their metabolism to dihydroxyeicosatrienoates (DHETs) is catalyzed by soluble epoxide hydrolase (sEH). After subarachnoid hemorrhage (SAH), EETs' pathway amplification may be a therapeutic target for the prevention of delayed cerebral ischemia (DCI). We conducted a double-blind, placebo-controlled, phase Ib randomized trial of GSK2256294, a pharmacologic inhibitor of sEH, to evaluate the safety profile and to assess biomarkers of neurovascular inflammation in patients with aneurysmal SAH.

METHODS:

Patients were randomly assigned to receive 10 mg of GSK2256294 or a placebo treatment once daily for 10 days, beginning within 72 hours after aneurysm rupture. The primary study end point was safety. Secondary end points included serum and cerebrospinal fluid (CSF) EETs-to-DHETs ratio, cytokine levels, and serum endothelial injury biomarkers, measured at day 7 and day 10 after SAH. Tertiary end points included neurologic status, disposition, length of stay, incidence of DCI, and mortality; these were assessed at hospital discharge and at 90 days.

RESULTS:

Ten patients received GSK2256294 and nine patients received a placebo. There were no adverse events related to the study drug. GSK2256294 administration resulted in a significant increase in the EET/DHET ratio at day 7 and day 10 in serum, but not in the CSF. There was a trend for decreased CSF inflammatory cytokines following GSK2256294 administration, but this did not reach statistical significance.

CONCLUSIONS:

GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov: NCT03318783.

01 Feb 2022·Prostaglandins & other lipid mediatorsQ3 · BIOLOGY

The soluble epoxide hydrolase inhibitor GSK2256294 decreases the proportion of adipose pro-inflammatory T cells

Q3 · BIOLOGY

Article

Author: Brown, Nancy J ; Wanjalla, Celestine N ; Pilkinton, Mark ; Pozzi, Ambra ; Ghoshal, Kakali ; Gabriel, Curtis L ; Bailin, Samuel S ; Warren, Christian M ; Kalams, Spyros A ; Koethe, John R ; Simmons, Joshua D ; Mashayekhi, Mona ; Luther, J Matthew

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

100 Deals associated with GSK-2256294

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Phase 2	-	GSK Plc	-
Obesity	Phase 1	GB	GSK Plc	16 Jan 2013
Pulmonary Disease, Chronic Obstructive	Phase 1	GB	GSK Plc	16 Jan 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03318783 (SUSHI, Pubmed \| Neurocrit Care) Manual	Phase 1	Aneurysm, Intracranial Berry, 1	19	GSK-2256294	jkmzxidufm(creepnzgng) = ppmfwwcooa vmutkzdxes (hmpaukzeiv )	Positive	01 Jun 2022
				Placebo	-
NCT03486223 (Pubmed \| Curr Hypertens Rep)	Phase 2	Insulin Resistance \| Prediabetic State \| Obesity	16	GSK2256294 10 mg QD	yswlvxptgj(govkfzinai) = vwpkftpgxk nfcnbyerbt (hmpxrzfwax )	-	30 Aug 2021
				Placebo	yswlvxptgj(govkfzinai) = uzimgfeltl nfcnbyerbt (hmpxrzfwax )
NCT03318783 (SUSHI, CTgov)	Phase 1/2	Subarachnoid Hemorrhage \| Endothelial dysfunction \| Brain Ischemia ... View more	20	GSK2256294 (GSK2256294)	bcvfvlzcpa(bvmznyhwgh) = ahagfuysuv jsgmcsihaf (yvlwbqkvwd, wvjzhrnhlj - ctqiqlsptv) View more	-	22 Jan 2021
				Placebo (Placebo)	bcvfvlzcpa(bvmznyhwgh) = vqcobmhygs jsgmcsihaf (yvlwbqkvwd, zyeeqjgyai - jllusiodag) View more
NCT01762774 (Pubmed) Manual	Phase 1	Pulmonary Disease, Chronic Obstructive \| Smoking	33	GSK2256294	rvugsyynje(qeqvopwxoq) = zzovipmvjk fdgveineso (yaimeesgje, 0.172) View more	Positive	01 Mar 2017
				Placebo	rvugsyynje(qeqvopwxoq) = ayakekbapg fdgveineso (yaimeesgje, 0.118) View more