| Literature DB >> 29233651 |
Hua Gong1, David S Weinstein1, Zhonghui Lu1, James J-W Duan1, Sylwia Stachura1, Lauren Haque1, Ananta Karmakar2, Hemalatha Hemagiri2, Dhanya Kumar Raut2, Arun Kumar Gupta2, Javed Khan1, Dan Camac1, John S Sack1, Andrew Pudzianowski1, Dauh-Rurng Wu1, Melissa Yarde1, Ding-Ren Shen1, Virna Borowski1, Jenny H Xie1, Huadong Sun1, Celia D'Arienzo1, Marta Dabros1, Michael A Galella1, Faye Wang1, Carolyn A Weigelt1, Qihong Zhao1, William Foster1, John E Somerville1, Luisa M Salter-Cid1, Joel C Barrish1, Percy H Carter1, T G Murali Dhar3.
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.Entities:
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Year: 2017 PMID： 29233651 DOI： 10.1016/j.bmcl.2017.12.006
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823