Design, Synthesis, and Pharmacological Evaluation of Benzimidazolo-thiazoles as Potent CXCR3 Antagonists with Therapeutic Potential in Autoimmune Diseases: Discovery of ACT-672125

The chemokine receptor CXCR3 allows the selective recruitment
of
innate and adaptive inflammatory immune cells into inflamed tissue.
CXCR3 ligands are secreted after exposure to pro-inflammatory cytokines.
Upon binding to CXCR3 ligands, CXCR3 expressing T-lymphocytes migrate
toward sites of inflammation and can promote tissue damage. Therefore,
antagonizing this receptor may provide clinical benefits for patients
suffering from autoimmune diseases characterized by high concentrations
of CXCR3 ligands. Herein, we report the second part of our CXCR3 discovery
program where we explored the benzimidazolo-thiazole core scaffold.
The optimization of potency and the mitigation of an hERG liability
are described. Further pharmacokinetic considerations led to the identification
of the potent CXCR3 antagonist ACT-672125 (29). The compound
showed good physicochemical properties and safety profile. In a proof-of-mechanism
model of lung inflammation, ACT-672125 inhibited the recruitment of
CXCR3 expressing T cells into the inflamed lung in a dose-dependent
manner.