Structure-Based Discovery Of Phenyl (3-Phenylpyrrolidin-3-Yi)Sulfones As Selective, Orally Active Ror Gamma T Inverse Agonists

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of ROR gamma t inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at Nl-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXR alpha, and LXR beta. Further optimization led to the discovery of (1R,40-44(R)-34(4-fluorophenyl)sulfony1)-3-(4-(perfluoropropan-2-yOphenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 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.