Discovery of Clinical Candidate ACT-777991, a Potent CXCR3 Antagonist for Antigen-Driven and Inflammatory Pathologies
Journal
Journal of Medicinal Chemistry
Author(s)
Year
2023
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.
INTRODUCTION CXCR3 is a G protein-coupled receptor from the CXC chemokine receptor family. It is expressed on adaptive and innate immune cells, for example, on subsets of T cells, B cells, NK cells, and antigen-presenting cells. 1 The CXCR3 receptor is rapidly upregulated following dendritic cell-induced T cell activation. 2 The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are produced by a number of cell types, such as endothelial cells and monocytes, upon exposure to proin-flammatory cytokines (e.g., IFN-γ, TNF-α, and IL-1β). 3,4 Binding of a ligand to CXCR3 induces signaling via an increase in intracellular calcium levels, resulting in the migration of CXCR3 cells along the ligand gradient to the site of inflammation. Since the CXCR3 axis is reported to be upregulated in inflamed tissues of patients with autoimmune diseases, several research and development programs aiming at blocking the receptor−ligand interaction have been conducted with small molecules. 5−10 In addition, eldelumab, a mono-clonal antibody targeting CXCL10, showed promising clinical outcome in patients with rheumatoid arthritis, on top of methotrexate, and as a single agent in patients with ulcerative colitis or Crohn’s disease. 11−14 We recently reported the discovery of ACT-660602 (1) and ACT-672125 (2), two potent and selective CXCR3 antagonists. 15,16 Both molecules showed efficacy in a proof of mechanism mouse model of acute lung inflammation. Despite excellent physicochemical and ADME properties, the two compounds were discontinued. During in vivo toxicology experiments with compound 2, a significant bilirubin increase was observed in rat and cynomolgus monkey leading to termination of the preclinical development program. Compound 1 was found to be metabolized exclusively by CYP2D6, a highly polymorphic CYP enzyme within the human population. Genetic variations in metabolizing enzymes may lead to increased or decreased clearance of the parent drug and consequently to highly variable plasma exposures in patients. 17−19 For example, for many antidepressants and antipsychotics that are CYP2D6 substrates, the plasma levels of the drug at the same dosage vary 5-to 20-fold, an important factor being polymorphism of the CYP2D6 enzyme. 20 Therefore, we aimed at identifying new CXCR3 antagonists with a metabolism not fully dependent on 2D6 and a safety profile suitable for chronic dosing. In addition, a higher potency in the receptor internalization (RI) assay in human blood was targeted.