6-Substituted quinolines as RORγt inverse agonists

We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). The synthesis of this class of ROR gamma t modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a ROR gamma t-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the ROR gamma t ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact. (C) 2017 Elsevier Ltd. All rights reserved.