Discovery of biaryls as RORγ inverse agonists by using structure-based design

ROR gamma plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, gamma delta T cells, and innate lymphoid cells. ROR gamma-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of ROR gamma have the potential of modulating inflammation. Our goal was to optimize two ROR gamma inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series. (C) 2016 Elsevier Ltd. All rights reserved.