Drug Discovery Chemistry Immunology, Idorsia Pharmaceuticals Ltd., Allschwil 4123, Switzerland.
DMPK, Idorsia Pharmaceuticals Ltd., Allschwil 4123, Switzerland.
J Med Chem. 2022 Sep 8;65(17):11513-11532. doi: 10.1021/acs.jmedchem.2c00675. Epub 2022 Aug 10.
The chemokine receptor CXCR3 is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies, in particular autoimmune diseases. It is activated by the three chemokine ligands CXCL9, CXCL10, and CXCL11 and enables the recruitment of immune cell subsets leading to damage of inflamed tissues. Starting from a high-throughput screening hit, we describe the iterative optimization of a chemical series culminating in the discovery of the selective CXCR3 antagonist ACT-660602 (). The careful structural modifications during the lead optimization phase led to a compound with high biological potency in inhibiting cell migration together with improvements of the metabolic stability and hERG issue. In a LPS-induced lung inflammation model in mice, ACT-660602 led to significantly reduced recruitment of the CXCR3 CD8 T cell in the bronchoalveolar lavage compartment when administered orally at a dose of 30 mg/kg.
趋化因子受体 CXCR3 是一种七次跨膜 G 蛋白偶联受体 (GPCR)，参与多种病理过程，特别是自身免疫性疾病。它被三种趋化因子配体 CXCL9、CXCL10 和 CXCL11 激活，并能够募集免疫细胞亚群，导致炎症组织损伤。本研究从高通量筛选命中化合物开始，描述了一个化学系列的迭代优化，最终发现了选择性 CXCR3 拮抗剂 ACT-660602 ()。在先导化合物优化阶段进行了仔细的结构修饰，导致在抑制细胞迁移方面具有高生物学效力的化合物，同时改善了代谢稳定性和 hERG 问题。在 LPS 诱导的小鼠肺炎症模型中，当以 30mg/kg 的剂量口服给予时，ACT-660602 可显著减少 CXCR3 CD8 T 细胞在支气管肺泡灌洗液中的募集。
