GLPG0974 is an oral, high-affinity, potent and selective free fatty acid receptor 2 (FFA2, GPR43, IC50 = 9nM) antagonist [1]. GLPG0974 inhibits neutrophil activation and migration by blocking the agonistic effect of short-chain fatty acids (SCFA) on FFA2, thereby exerting anti-inflammatory effects [2-3]. GLPG0974 is commonly used in inflammatory diseases [4].
In SH-SY5Y cells, treatment with GLPG0974 (100μM; 24h) significantly abolished the neuroprotective effect of a specific GPR43 agonist [5]. In myocardial cells, GLPG0974 (10μM; 5 minutes) prevents acetate-induced inhibition of myocardial contraction [6]. In IPEC-J2 cells, GLPG0974 (500nM; 24h) can restore PEDV replication in butyrate-pretreated IPEC-J2 cells [7].
In C57BL/6 mice, treated with GLPG0974 (1mg/kg; ig; 5 weeks) showed enhanced motor skills, increased numbers of fecal pellets, and significant improvement in constipation symptoms [8]. In the sepsis associated encephalopathy (SAE) mouse model established by cecal ligation and puncture (CLP) surgery, GLPG0974 (1mg/kg; po; 24d) can reverse the cognitive protective and anti-neuroinflammatory effects of short-chain fatty acids [9]. In high-fat-diet (HFD) fed mice model, abdominal fat in mice significantly increased after intragastric administration of GLPG0974 (1mg/kg; ig; 24d) [10].
References:
[1]. Namour F, Galien R, Van Kaem T, et al. Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. British journal of clinical pharmacology. 2016 Jul; 82(1): 139-148.
[2]. Pizzonero M, Dupont S, Babel M, et al. Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. Journal of medicinal chemistry. 2014 Dec 11; 57(23): 10044-10057.
[3]. Wenzel TJ, Gates EJ, Ranger AL, et al. Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Molecular and Cellular Neuroscience. 2020 Jun 1; 105: 103493.
[4]. Vermeire S, Kojecky V, Knoflícek V, et al. GLPG0974, an FFA2 antagonist, in ulcerative colitis: efficacy and safety in a multicenter proof-of-concept study. J. Crohn’s Colitis. 2015 Feb 1; 9(Suppl 1): S39.
[5]. Saikachain N, Sungkaworn T, Muanprasat C, et al. Neuroprotective effect of short‐chain fatty acids against oxidative stress‐induced SH‐SY5Y injury via GPR43‐dependent pathway. Journal of Neurochemistry. 2023 Jul; 166(2): 201-214.
[6]. Jiang X, Zhang Y, Zhang H, et al. Acetate suppresses myocardial contraction via the short-chain fatty acid receptor GPR43. Frontiers in Physiology. 2022 Dec 16; 13: 1111156.
[7]. He H, Fan X, Shen H, et al. Butyrate limits the replication of porcine epidemic diarrhea virus in intestine epithelial cells by enhancing GPR43-mediated IFN-III production. Frontiers in microbiology. 2023 Jan 20; 14: 1091807.
[8]. Qu Y, An K, Wang D, et al. Short-Chain Fatty Acid Aggregates Alpha-Synuclein Accumulation and Neuroinflammation via GPR43-NLRP3 Signaling Pathway in a Model Parkinson’s Disease. Molecular Neurobiology. 2025 Feb 4: 1-4.
[9]. Li H, Bao H, Jiang L, et al. Short chain fatty acids protect the cognitive function of sepsis associated encephalopathy mice via GPR43. Frontiers in Neurology 13: 909436 [Internet]. 2022
[10]. Pham MT, Tran TD, Zayabaatar E. Leuconostoc mesenteroides utilizes glucose fermentation to produce electricity and ameliorates high-fat diet-induced abdominal fat mass. Archives of Microbiology. 2022 Nov; 204(11): 670.
GLPG0974是一种口服、高亲和力、强效且选择性的游离脂肪酸受体2（FFA2, GPR43，IC50 = 9nM）拮抗剂 [1]。GLPG0974通过阻断短链脂肪酸（SCFA）对FFA2的激动作用来抑制中性粒细胞活化和迁移，从而发挥抗炎作用 [2-3]。GLPG0974常用于治疗炎症性疾病 [4]。
在SH-SY5Y细胞中，GLPG0974（100μM；24h）处理可显著消除特定GPR43激动剂的神经保护作用 [5]。在心肌细胞中，GLPG0974（10μM；5分钟）可阻止醋酸盐诱导的心肌收缩抑制 [6]。在IPEC-J2细胞中，GLPG0974（500nM；24h）可恢复经丁酸预处理的IPEC-J2细胞中PEDV的复制 [7]。
在C57BL/6小鼠中，用GLPG0974（1mg/kg；ig；5周）治疗后，小鼠的运动技能增强，粪便颗粒数量增加，便秘症状显著改善 [8]。在通过盲肠结扎穿刺（CLP）手术建立的脓毒症相关性脑病（SAE）小鼠模型中，GLPG0974（1mg/kg；po；24d）可逆转短链脂肪酸的认知保护和抗神经炎作用 [9]。在高脂饮食（HFD）喂养的小鼠模型中，小鼠灌胃GLPG0974（1mg/kg；ig；24d）后，腹部脂肪显著增加 [10]。