Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the Chemokine Receptor CXCR3 for Autoimmune Diseases,Journal of Medicinal Chemistry

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Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the Chemokine Receptor CXCR3 for Autoimmune Diseases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-08-10 , DOI: 10.1021/acs.jmedchem.2c00675
Emmanuel A Meyer ₁ , Päivi Äänismaa ₂ , Sylvie Froidevaux ₃ , Marcel Keller ₄ , Luca Piali ₅ , Eva Caroff ₁

Affiliation

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 (9j). 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.

中文翻译：

ACT-660602 的发现和体内评估：一种针对自身免疫性疾病的趋化因子受体 CXCR3 的强效和选择性拮抗剂

趋化因子受体 CXCR3 是一种七跨膜 G 蛋白偶联受体 (GPCR)，涉及各种病理，特别是自身免疫性疾病。它由三种趋化因子配体 CXCL9、CXCL10 和 CXCL11 激活，并能够募集免疫细胞亚群，从而导致炎症组织受损。从高通量筛选命中开始，我们描述了化学系列的迭代优化，最终发现了选择性 CXCR3 拮抗剂 ACT-660602 ( 9j）。在先导优化阶段仔细的结构修饰导致化合物在抑制细胞迁移方面具有高生物效力，同时改善了代谢稳定性和 hERG 问题。在 LPS 诱导的小鼠肺部炎症模型中，当以 30 mg/kg 的剂量口服给药时，ACT-660602 导致支气管肺泡灌洗室中 CXCR3 ⁺ CD8 ^{+ T 细胞的募集显着减少。}

更新日期：2022-08-10

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