Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists

Abstract

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide <b>1</b>. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at <i>N</i>1-position of the pyrrolidine ring and perfluoroisopropyl group at <i>para</i>-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRβ. Further optimization led to the discovery of (1<i>R</i>,4r)-4-((<i>R</i>)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (<b>26</b>), which displayed excellent selectivity, desirable liability and pharmacokinetic properties <i>in vitro</i>, and a good pharmacokinetic profile in mouse. Oral administration of <b>26</b> demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.