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

  • J Med Chem. 2023 Mar 23;66(6):4179-4196. doi: 10.1021/acs.jmedchem.3c00074.
Emmanuel A Meyer  1 ,  Päivi Äänismaa  2 ,  Eric A Ertel  3 ,  Eva Hühn  2 ,  Daniel S Strasser  4 ,  Markus Rey  5 ,  Mark J Murphy  6 ,  Marianne M Martinic  7 ,  Laetitia Pouzol  7 ,  Sylvie Froidevaux  8 ,  Marcel P Keller  6 ,  Eva Caroff  1
Affiliations
  • 1. Chemistry Immunology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 2. DMPK, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 3. Electrophysiology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 4. Translational Biomarkers, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 5. Cardiovascular Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 6. Biology Immunology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 7. Pharmacology Immunology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland.
  • 8. Idorsia Pharmaceuticals Ltd, Bendorf 68480, France.
PMID: 36883854 DOI: 10.1021/acs.jmedchem.3c00074
Abstract

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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