Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357
Christian Harcken, Johanna Csengery, Michael Turner, Lifen Wu, Shuang Liang, Robert Sibley, Steven Brunette, Mark E. Labadia, Kathleen Hoyt, A. Wayne, Thomas Wieckowski, Gregg Davis, Mark Panzenbeck, Donald Souza, Stanley Kugler, Donna Terenzio, Delphine Collin, Dustin Smith, Ryan M. Fryer, Yin‐Chao Tseng, Jörg P. Hehn, Kim Fletcher, Robert Hughes
Abstract
The interleukin (IL)-23/T helper (Th)17 axis plays a critical role in autoimmune diseases, and there is an increasing number of biologic therapies that target IL-23 and IL-17. The transcription factor retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is important for the activation and differentiation of Th17 cells and thus is an attractive pharmacologic target for the treatment of Th17-mediated diseases. A novel series of pyrazinone RORγ antagonists was discovered through hybridization of two distinct screening hits and scaffold hopping. The series offers attractive potency and selectivity in combination with favorable druglike properties, such as metabolic stability and aqueous solubility. Lead optimization identified a clinical candidate, compound (S)-11 (BI 730357), for the treatment of autoimmune diseases.