FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.

中文翻译：

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作为游离脂肪酸受体 2 (FFA2) 拮抗剂的氮杂环丁烷化学系列的发现和优化：从命中到临床

FFA2，也称为 GPR43，是短链脂肪酸的 G 蛋白偶联受体，参与炎症反应的介导。一类氮杂环丁烷被开发为有效的 FFA2 拮抗剂。对具有中等效力和次优 ADME 特性的早期命中进行多参数优化，从而鉴定出几种对受体具有纳摩尔效力并结合出色药代动力学 (PK) 参数的化合物。最先进的化合物，4-[[( R )-1-(benzo[ b ]噻吩-3-羰基)-2-甲基-氮杂环丁烷-2-羰基]-(3-氯-苄基)-氨基]-丁酸酸99(GLPG0974) 能够在体外强烈抑制醋酸盐诱导的中性粒细胞迁移，并在人全血测定中显示出抑制基于中性粒细胞的药效学 (PD) 标志物 CD11b 激活特异性表位 [AE] 的能力。总之，这些数据支持99向下一阶段的进展，成为第一个到达临床的 FFA2 拮抗剂。