Discovery and Characterization of Zelnecirnon (RPT193), a Potent and Selective CCR4 Antagonist for Allergic Disorders

The CCR4 pathway plays an important role in a variety of allergic disorders. This receptor is primarily expressed on CD4+ cells, in particular T helper type 2 (Th2) immune cells, allowing these cells to migrate to the inflamed tissue and exacerbate the disease by the production of proinflammatory cytokines such as IL-4, IL-5, and IL-13. Antagonism of the CCR4 receptor is an attractive way to restrict this migration, which offers potential disease modification. Herein we report the discovery of Zelnecirnon (RPT193), a potent and selective small-molecule CCR4 antagonist. Zelnecirnon can effectively inhibit CCR4-induced chemotaxis, has attractive DMPK and drug-like properties, and can reduce CCR4 receptor surface expression. In an in vivo model of atopic dermatitis, Zelnecirnon demonstrated efficacy similar to those of approved biologics in this indication, thus demonstrating the proof of concept for this mechanism and its potential as an effective oral alternative.