期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 2, 页码 85-93出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.12.006
关键词
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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.
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