Delving into the Latest Updates on GLPG-0974 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

FFAR2

Mechanism

FFAR2 antagonists(Free fatty acid receptor 2 antagonists)

Therapeutic Areas

Digestive System Disorders

Active Indication-

Inactive Indication

Colitis, Ulcerative

Originator Organization

Galapagos NV

Active Organization-

Inactive Organization

Galapagos NV

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC25H25ClN2O4S

InChIKeyMPMKMQHJHDHPBE-RUZDIDTESA-N

CAS Registry1391076-61-1

Exploratory, Phase II, Randomized, Double-blind, Placebo-controlled, Proof-of-Concept study to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of GLPG0974 in subjects with mild to moderate Ulcerative Colitis - Proof-of-concept oral dose, safety, tolerability, efficacy, PK and PD study

Start Date16 May 2013

Sponsor / Collaborator

Galapagos NV

NCT01829321 / CompletedPhase 2

Exploratory, Phase II, Randomized, Double-blind, Placebo-controlled, Proof-of-Concept Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of GLPG0974 in Subjects With Mild to Moderate Ulcerative Colitis

Approximately 45 patients suffering from mild to moderate ulcerative colitis will be examined for any side effects (safety and tolerability) that may occur when taking GLPG0974 or matching placebo (2:1 ratio) for 28 days.
During the course of the study, patients will also be evaluated for improvement of disease activity by different efficacy measures, the amount of GLPG0974 present in the blood determined (PK) and the effects of GLPG0974 on selected biomarkers (PD) in the blood, colon biopsies and faeces will be explored.

Start Date01 Apr 2013

Sponsor / Collaborator

Galapagos NV

NCT01721980 / CompletedPhase 1

Double-blind, Randomized, Placebo-controlled Study for the Assessment of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of GLPG0974 in Healthy Male Subjects

The purpose of this study is to evaluate the safety and tolerability after multiple ascending oral doses of GLPG0974 given to healthy male subjects for 14 days, compared to placebo.
Furthermore, during the course of the study, the amount of GLPG0974 present in the blood and urine (pharmacokinetics) as well as the effects of GLPG0974 on mechanism of action-related parameters in the blood and stool samples (pharmacodynamics) will be characterized compared to placebo.
Also, the effect of the compound on glucose tolerance will be explored as well as the potential of cytochrome P450 (CYP)3A4 induction by repeated dosing with GLPG0974.

Start Date01 Oct 2012

Sponsor / Collaborator

Galapagos NV

100 Clinical Results associated with GLPG-0974

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100 Translational Medicine associated with GLPG-0974

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100 Patents (Medical) associated with GLPG-0974

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17

Literatures (Medical) associated with GLPG-0974

01 Dec 2023·Pharmacological Research

Protective effect of microbiota-derived short chain fatty acids on vascular dysfunction in mice with systemic lupus erythematosus induced by toll like receptor 7 activation

Article

Author: Sánchez, Manuel ; González-Correa, Cristina ; Miñano, Sofía ; Robles-Vera, Iñaki ; Gómez-Guzmán, Manuel ; Romero, Miguel ; de la Visitación, Néstor ; Moleón, Javier ; Toral, Marta ; Barranco, Antonio Manuel ; Riesco, Pedro ; Duarte, Juan ; Guerra-Hernández, Eduardo

Our objective was to investigate whether short-chain fatty acids (SCFAs), specifically acetate and butyrate, could prevent vascular dysfunction and elevated blood pressure (BP) in mice with systemic lupus erythematosus (SLE) induced by TLR7 activation using imiquimod (IMQ). Treatment with both SCFAs and dietary fibers rich in resistant starch (RS) or inulin-type fructans (ITF) effectively prevented the development of hypertension and cardiac hypertrophy. Additionally, these treatments improved aortic relaxation induced by acetylcholine and mitigated vascular oxidative stress. Acetate and butyrate treatments also contributed to the maintenance of colonic integrity, reduced endotoxemia, and decreased the proportion of helper T (Th)17 cells in mesenteric lymph nodes (MLNs), blood, and aorta in TLR7-induced SLE mice. The observed changes in MLNs were correlated with increased levels of GPR43 mRNA in mice treated with acetate and increased GPR41 levels along with decreased histone deacetylase (HDAC)- 3 levels in mice treated with butyrate. Notably, the effects attributed to acetate, but not butyrate, were nullified when co-administered with the GPR43 antagonist GLPG-0974. T cell priming and differentiation into Th17 cells in MLNs, as well as increased Th17 cell infiltration, were linked to aortic endothelial dysfunction and hypertension subsequent to the transfer of faecal microbiota from IMQ-treated mice to germ-free (GF) mice. These effects were counteracted in GF mice through treatment with either acetate or butyrate. To conclude, these findings underscore the potential of SCFA consumption in averting hypertension by restoring balance to the interplay between the gut, immune system, and vascular wall in SLE induced by TLR7 activation.

01 Aug 2023·Journal of applied microbiology

Houpo paiqi mixture promotes intestinal motility in constipated rats by modulating gut microbiota and activating 5-HT-cAMP-PKA signal pathway.

Article

Author: Zhao, Luqing ; Zhang, Shengsheng ; Zhang, Weixi ; Lu, Xiaofang ; Wang, Ruixin

AIMSConstipation is a common functional gastrointestinal disorder, which needs more effective treatment approaches. Houpo Paiqi Mixture (HPPQM) is a type of Chinese patent medicine developed from a classical formula that has been widely applied to the treatment of intestinal motility disorder. Here we aim to assess the effectiveness of HPPQM in the treatment of constipation in rat models and its potential mechanism.METHODS AND RESULTSUPLC-MS/MS was performed to investigate the chemical component of HPPQM. Rats were randomly divided into normal control, constipation model (CM), HPPQM (low, middle and high dose) and mosapride groups. Loperamide 8 mg/kg was given orally to induce CM. The small intestine motility, colonic contraction, rectum propulsion, and histological feature of the colon were significantly improved in HPPQM group, compared with CM group (P < 0.05). Results of 16S rRNA sequencing revealed that HPPQM treatment strikingly restructured intestinal microbiota in constipated rats by increasing the relative abundances of Bacteroides and Akkermansia and decreasing the relative abundances of Prevotella and Lactobacillus. The levels of GPR43, 5-HT, 5-HT4R, cAMP, PKA were decreased while SERT was increased in constipated rats (P < 0.05), which could be restored to normal levels by treatment with HPPQM (P < 0.05). Differences in amplitude between experimental CLSMs (with HPPQM added) and control CLSMs were discovered, starting at the concentration of 40 nL/mL (P < 0.05). It was found that GLPG0974 and GR113808 could significantly reduce this reactivity (P < 0.05).CONCLUSIONSHPPQM manifested a curative effect in constipated rats by promoting intestinal motility. The underlying mechanisms might be related to modulating gut microbiota and activating 5-HT-cAMP-PKA signal pathway.

01 Jan 2023·The FASEB Journal

Constitutively active GPR43 is crucial for proper leukocyte differentiation

Article

Author: Iwata, Kurumi ; Shindou, Hideo ; Nakamura, Shou ; Yanagida, Keisuke ; Inoue, Asuka ; Miyasato, Sosuke ; Mura, Reika ; Kawahara, Masahiro ; Nagamune, Teruyuki ; Yamaguchi, Satoshi ; Aoki, Junken ; Nakamura, Motonao ; Shimizu, Takao ; Nagata, Yosuke

The G protein-coupled receptors, GPR43 (free fatty acid receptor 2, FFA2) and GPR41 (free fatty acid receptor 3, FFA3), are activated by short-chain fatty acids produced under various conditions, including microbial fermentation of carbohydrates. Previous studies have implicated this receptor energy homeostasis and immune responses as well as in cell growth arrest and apoptosis. Here, we observed the expression of both receptors in human blood cells and a remarkable enhancement in leukemia cell lines (HL-60, U937, and THP-1 cells) during differentiation. A reporter assay revealed that GPR43 is coupled with Gα_i and Gα_12/13 and is constitutively active without any stimuli. Specific blockers of GPR43, GLPG0974 and CATPB function as inverse agonists because treatment with these compounds significantly reduces constitutive activity. In HL-60 cells, enhanced expression of GPR43 led to growth arrest through Gα_12/13 . In addition, the blockage of GPR43 activity in these cells significantly impaired their adherent properties due to the reduction of adhesion molecules. We further revealed that enhanced GPR43 activity induces F-actin formation. However, the activity of GPR43 did not contribute to butyrate-induced apoptosis in differentiated HL-60 cells because of the ineffectiveness of the inverse agonist on cell death. Collectively, these results suggest that GPR43, which possesses constitutive activity, is crucial for growth arrest, followed by the proper differentiation of leukocytes.

100 Deals associated with GLPG-0974

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External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	BE	Galapagos NV	01 Apr 2013
Colitis, Ulcerative	Phase 2	LV	Galapagos NV	01 Apr 2013
Colitis, Ulcerative	Phase 2	SK	Galapagos NV	01 Apr 2013
Colitis, Ulcerative	Phase 2	CZ	Galapagos NV	01 Apr 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01496937 (Pubmed \| Br J Clin Pharmacol) Manual	Phase 1	-	-	GLPG0974	(btjqvgrbwc) = daily dose of 400 mg bvjsyggbry (qzkqtnyojg )	Positive	01 Jul 2016
NCT01496937 (DOP070, ECCO2014)	Phase 1	Inflammation	-	GLPG0974	cylhonrgbk(yzuoyweqqc) = GLPG0974 substantially inhibited acetate-stimulated neutrophil activation in whole blood guzesdyxfs (jlxgghtoav ) View more	Positive	01 Feb 2014