Identification and biological evaluation of thiazole-based inverse agonists of RORγt

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. ROR gamma t lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of ROR gamma t drug discovery. We describe the discovery and evaluation of a new class of potent and selective ROR gamma t inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for ROR gamma t inhibition with this series. (C) 2018 Elsevier Ltd. All rights reserved.