GLPG1205

GLPG1205 is a novel, orally active GPR84 (G-protein-coupled receptor) antagonist. GLPG1205 reduces the release of cytokines (such as IL-8, IL-12, and TNF-α) by inhibiting the GPR84-mediated inflammatory signaling pathway^[1-2]. GLPG1205 can be used in research on diseases such as idiopathic pulmonary fibrosis and asthma^[3-4].

In vitro, human neutrophils, monocytes, and monocyte-derived macrophages were pretreated with GLPG1205 (0.5-1μM) for 4-5 minutes, followed by stimulation with the GPR84-selective agonist ZQ16 (0.5-1μM). GLPG1205 completely inhibited the ZQ16-induced intracellular Ca²⁺ increase and significantly suppressed the ZQ16-induced reactive oxygen species (ROS) production^[5]. THP-1 cells were pretreated with GLPG1205 (20μM) for 20 minutes, which completely inhibited the 6-OAU-induced ROS production^[6].

In vivo, C57BL/6J wild-type mice were orally administered GLPG1205 (30mg/kg) one hour after concanavalin A (Con A) injection. GLPG1205 significantly reduced serum ALT and AST levels, decreased the proportion of Kupffer cells and infiltrating monocytes in the liver, and alleviated Con A-induced immune-mediated liver injury^[7]. B16-OVA or B16-F10 tumor-bearing mice were orally administered GLPG1205 (30mg/kg) once daily for three days following adoptive T cell transfer. GLPG1205 significantly enhanced the antitumor efficacy of the adoptive CD8⁺ T cells and significantly reduced tumor volume^[8].

References:
[1] Timmis H, Van Kaem T, Desrivot J, et al. GLPG1205, a GPR84 Modulator: Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Subjects. Clin Pharmacol Drug Dev. 2021 Sep;10(9):994-1006.
[2] Desrivot J, Van Kaem T, Allamassey L, et al. Effect of GLPG1205, a GPR84 Modulator, on CYP2C9, CYP2C19, and CYP1A2 Enzymes: In Vitro and Phase 1 Studies. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1007-1017.
[3] Donovan C, Thorpe AE, Gomez HM, et al. The GPR84 Antagonist GLPG1205 Reduces Features of Disease in Experimental Severe Asthma. Am J Respir Cell Mol Biol. 2024 May;70(5):424-427.
[4] Strambu IR, Seemayer CA, Fagard LMA, et al. GLPG1205 for idiopathic pulmonary fibrosis: a phase 2 randomised placebo-controlled trial. Eur Respir J. 2023 Mar 2;61(3):2201794.
[5] Schwarzfischer M, Walker MR, Curcio M, et al. Synthetic GPR84 Agonists in Colorectal Cancer: Effective in THP-1 Cells but Ineffective in BMDMs and MC38 Mouse Tumor Models. Int J Mol Sci. 2025 Jan 9;26(2):490.
[6] Sundqvist M, Christenson K, Holdfeldt A, et al. Similarities and differences between the responses induced in human phagocytes through activation of the medium chain fatty acid receptor GPR84 and the short chain fatty acid receptor FFA2R. Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):695-708.
[7] Zheng Y, Wang Y, Xu Y, et al. Targeting GPR84 to alleviate acute immune-mediated liver injury. Mol Med. 2025 May 14;31(1):187.
[8] Philbrook P, Dean MJ, Sanchez-Pino MD, et al. Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming. Cancer Immunol Res. 2026 Jan 20:10.1158/2326-6066.CIR-25-0695.

GLPG1205是一种新型的、具有口服活性的GPR84（G蛋白偶联受体）拮抗剂。GLPG1205可通过抑制GPR84介导的炎症信号通路来减少细胞因子（如IL-8、IL-12和TNF-α）的释放^[1-2]。GLPG1205可用于特发性肺纤维化和哮喘等疾病的研究^[3-4]。

在体外，GLPG1205（0.5-1μM）预处理人类嗜中性粒细胞、单核细胞及单核细胞衍生的巨噬细胞4-5分钟，随后以GPR84选择性激动剂ZQ16（0.5-1μM）刺激。GLPG1205可完全抑制ZQ16诱导的细胞内Ca²⁺升高，并显著抑制其诱导的活性氧（ROS）产生^[5]。GLPG1205（20μM）预处理THP-1细胞20min，可完全抑制6-OAU诱导的ROS产生^[6]。

在体内，GLPG1205（30mg/kg）在注射concanavalin A（Con A）1小时后通过口服灌胃给予C57BL/6J野生型小鼠。GLPG1205显著降低了血清ALT和AST水平，减少了肝脏中Kupffer细胞和浸润单核细胞的比例，并减轻了Con A诱导的免疫性肝损伤^[7]。GLPG1205（30mg/kg）在过继性T细胞转移后通过口服灌胃每日一次给予B16-OVA或B16-F10肿瘤小鼠，持续三天。GLPG1205显著增强了过继性CD8+ T细胞的抗肿瘤效果，并显著降低了肿瘤体积^[8]。