Discovery and characterization of CD12681, a potent RORγ inverse agonist, preclinical candidate for the topical treatment of psoriasis.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor ROR has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent ROR inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with invivo activity in an IL-23-induced mouse skin inflammation model.