GLPG1205 is a Selective GPR84 Antagonist with Anti-Inflammatory Activity

GLPG1205 is a Selective GPR84 Antagonist with Anti-Inflammatory Activity

GPR84 is a de-orphanized member of the G-protein coupled receptor (GPCR) family, it can recognize medium-chain fatty acids. GPR84 plays an important role in inflammation.
In this article, we will introduce a potent, selective and orally active GPR84 antagonist GLPG1205. Besides, we will describe this compound’s properties in vitro and in vivo.

Firstly, in vitro, the receptor-selective antagonist GLPG1205 together with ZQ16, a potent GPR84 selective agonist are identified in a high throughput screening study. Human neutrophils, monocytes and monocyte-derived macrophages (MDMs) can functionally express GPR84.

The agonist ZQ16 can trigger the G-protein coupled PLC-IP3-Ca2+ signaling pathway. At the same time, It mobilizes intracellular granules, chemotactic migration, as well as an assembly of ROS generating NADPH-oxidase.
However, GLPG1205 completely inhibits ZQ16-induced [Ca2+] I response in neutrophils. Besides, the selectivity of this inhibitor for GPR84 shows that GLPG1205 does not affect the FPR1- and FFA2R-mediated Ca2+ responses. In monocytes, there shows an identical inhibition pattern. GLPG1205 (1 μM; for 5 min) completely blocks the ROS-response induced by the GPR84-agonist in the macrophages.
Following, GLPG1205 can antagonize ZQ16-induced ROS with an IC50 value of 15 nM in TNFα primed neutrophils. Moreover, GLPG1205 has no response on FFA2R agonist Cmp1and he FPR1 agonist fMLF-induced ROS. this furtherly strengthens the selectivity of the antagonist GLPG1205 for GPR84.

GLPG1205 is a Selective GPR84A ntagonist with Anti Inflammatory Activity 2020 01 08 - GLPG1205 is a Selective GPR84 Antagonist with Anti-Inflammatory Activity

Lastly, we will give some examples of activity in vivo of GLPG1205.

In the idiopathic pulmonary fibrosis (IPF) model, GLPG1250 (orally administration; 30mg/kg; twice daily) for 2 weeks, start from 7 days post-challenge greatly reduces the Ashcroft score.

In the irradiation model, GLPG1250 (orally administration; 30mg/kg; once daily) starts from 18 weeks post-irradiation, significantly reduces college deposition in the mouse lung. Additionally, GLPG1250 inhibits the increase in MnSOD in lung bronchial epithelial cells and parenchymal macrophages.

In a mouse IBD model (DSS), GLPG1205 dose-dependently decreases disease activity, histological activity, the neutrophil influx, and colonic MPO content.
In summary, GLPG1205 is potent and selective GPR84 (a G-protein-coupled receptor) antagonist. Additionally, it has anti-inflammatory activity and is used for the treatment of pulmonary fibrosis.

[1]. Sundqvist M, et al. Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):695-708.
[4]. F.Vanhoutte, et al. Human safety, pharmacokinetics, and pharmacodynamics.

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