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. Issue 2 (15th January 2018)

• Record Type: Journal Article
• Authors: Gong, Hua; Weinstein, David S.; Lu, Zhonghui; Duan, James J.-W.; Stachura, Sylwia; Haque, Lauren; Karmakar, Ananta; Hemagiri, Hemalatha; Raut, Dhanya Kumar; Gupta, Arun Kumar; Khan, Javed; Camac, Dan; Sack, John S.; Pudzianowski, Andrew; Wu, Dauh-Rurng; Yarde, Melissa; Shen, Ding-Ren; Borowski, Virna; Xie, Jenny H.; Sun, Huadong; D'Arienzo, Celia; Dabros, Marta; Galella, Michael A.; Wang, Faye; Weigelt, Carolyn A.; Zhao, Qihong; Foster, William; Somerville, John E.; Salter-Cid, Luisa M.; Barrish, Joel C.; Carter, Percy H.; Dhar, T.G. Murali;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 2(2018)
• Page Start: 85
• Page End: 93
• Publication Date: 2018-01-15
• Subjects: ROR retinoic acid-related orphan receptor -- PXR pregnane X receptor -- LXR liver X receptor -- IBD inflammatory bowel disease -- RA rheumatoid arthritis -- MS multiple sclerosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.12.006
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.