期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 6, 页码 4179-4196出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00074
关键词
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The CXCR3 chemokine receptor plays a crucial role in immune response and inflammatory processes. In this study, a novel clinical compound called ACT-777991 was discovered as a potent and selective CXCR3 antagonist. It showed dose-dependent efficacy and target engagement in a mouse model of acute lung inflammation, indicating its potential therapeutic value.
The CXCR3 chemokine receptor is a G protein-coupled receptor mainly expressed on immune cells from the lymphoid lineage, including activated T cells. Binding of its inducible chemokine ligands CXCL9, CXCL10, and CXCL11 leads to downstream signaling events and the migration of activated T cells to sites of inflammation. Herein, we report the third part of our CXCR3 antagonist program in the field of autoimmunity, culminating in the discovery of the clinical compound ACT-777991 (8a). A previously disclosed advanced molecule was exclusively metabolized by the CYP2D6 enzyme, and options to address the issue are described. ACT-777991 is a highly potent, insurmountable, and selective CXCR3 antagonist that showed dose-dependent efficacy and target engagement in a mouse model of acute lung inflammation. The excellent properties and safety profile warranted progress in the clinics.
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