Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent ROR gamma t inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor alpha (LXR alpha). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydro-quinoline sulfonamide analogs which completely dialed out LXR alpha activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y-max in the PXR assay for long term preclinical pharmacokinetic (PK) studies. (C) 2017 Elsevier Ltd. All rights reserved.