A Drug with Lipophilicity-Dependent Potency Can Be Metabolically Stable: Discovery of a Potent and Selective Retinoic Acid Receptor-Related Orphan Receptor C2 (RORC2) Inverse Agonist as an Orally Bioavailable Anti-Inflammatory Agent

IL-17 drives an amplification mechanism in inflammatory diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. The production of IL-17 depends on the activity of RORC2 in immune cells, which suggests that RORC2 inverse agonists are capable of anti-inflammatory therapy by reducing IL-17 levels. However, oral delivery of inverse agonists remains a challenge since the binding pocket of RORC2 prefers to accommodate lipophilic ligands, which tend to have poor metabolic stability. This Viewpoint discusses recent results published in this journal that identified a potent, selective, and orally bioavailable RORC2 inverse agonist as an anti-inflammatory agent, optimized from a high-throughput screening (HTS) hit through a combination of de novo and structure-guided design.