Synthesis of dihydroimidazole tethered imidazolinethiones and their activity as novel antagonists of the nuclear retinoic acid receptor-related orphan receptors (RORs)

Targeting the transcriptional activity of nuclear hormone receptors has proven an effective strategy to treat certain human diseases, and they have become a major focus point to develop novel therapies for the treatment of cancer, inflammation, autoimmune diseases, metabolic disorders, and others. One family of nuclear receptors that has attracted most interest in recent years is the retinoic acid receptor-related orphan receptors (RORs), in particular ROR gamma. ROR gamma is a critical regulator of the immune system and ROR gamma antagonists have shown activity in animal models of inflammatory autoimmune diseases. Here we present the synthesis and biological evaluation of dihydroimidazole tethered imidazolinethiones. We have identified several dual ROR gamma/alpha and pan-ROR antagonists with significant activity in cellular assays that could serve as starting points for future optimization efforts to generate potent and selective ROR gamma modulators. (C) 2017 Published by Elsevier Ltd.