AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2

Abstract

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist <b>2</b>. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (<b>20</b>), which combined potent inhibition of IL-17A secretion from primary human T_H17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical <i>in vivo</i> studies, compound <b>20</b> reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, <b>20</b> was progressed to phase 1 clinical studies.