Discovery of Clinical Candidate ACT-777991, a Potent CXCR3 Antagonist for Antigen-Driven and Inflammatory Pathologies

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.