Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt

Retinoic acid receptor-related orphan nuclear receptor gamma t (ROR gamma t) is a key transcription factor for the development of Th17 cells. Inhibiting ROR gamma t activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as ROR gamma t antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for ROR beta. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards ROR gamma t and ROR beta devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORb and its biology. (C) 2014 Elsevier Ltd. All rights reserved.