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. 2018 Jan 15;28(2):85-93.
doi: 10.1016/j.bmcl.2017.12.006. Epub 2017 Dec 5.

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

Hua Gong  1 , David S Weinstein  1 , Zhonghui Lu  1 , James J-W Duan  1 , Sylwia Stachura  1 , Lauren Haque  1 , Ananta Karmakar  2 , Hemalatha Hemagiri  2 , Dhanya Kumar Raut  2 , Arun Kumar Gupta  2 , Javed Khan  1 , Dan Camac  1 , John S Sack  1 , Andrew Pudzianowski  1 , Dauh-Rurng Wu  1 , Melissa Yarde  1 , Ding-Ren Shen  1 , Virna Borowski  1 , Jenny H Xie  1 , Huadong Sun  1 , Celia D'Arienzo  1 , Marta Dabros  1 , Michael A Galella  1 , Faye Wang  1 , Carolyn A Weigelt  1 , Qihong Zhao  1 , William Foster  1 , John E Somerville  1 , Luisa M Salter-Cid  1 , Joel C Barrish  1 , Percy H Carter  1 , T G Murali Dhar  3
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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

Hua Gong et al. Bioorg Med Chem Lett. .

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 compound 35 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.

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