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

被引：32

作者：

Gong, Hua ^{[1
]}

Weinstein, David S. ^{[1
]}

Lu, Zhonghui ^{[1
]}

Duan, James J. -W. ^{[1
]}

Stachura, Sylwia ^{[1
]}

Haque, Lauren ^{[1
]}

Karmakar, Ananta ^{[2
]}

Hemagiri, Hemalatha ^{[2
]}

Raut, Dhanya Kumar ^{[2
]}

Gupta, Arun Kumar ^{[2
]}

Khan, Javed ^{[1
]}

Camac, Dan ^{[1
]}

Sack, John S. ^{[1
]}

Pudzianowski, Andrew ^{[1
]}

Dauh-Rurng Wu ^{[1
]}

Yarde, Melissa ^{[1
]}

Shen, Ding-Ren ^{[1
]}

Borowski, Virna ^{[1
]}

Xie, Jenny H. ^{[1
]}

Sun, Huadong ^{[1
]}

D'Arienzo, Celia ^{[1
]}

Dabros, Marta ^{[1
]}

Galella, Michael A. ^{[1
]}

Wang, Faye ^{[1
]}

Weigelt, Carolyn A. ^{[1
]}

Zhao, Qihong ^{[1
]}

Foster, William ^{[1
]}

Somerville, John E. ^{[1
]}

Salter-Cid, Luisa M. ^{[1
]}

Barrish, Joel C. ^{[1
]}

Carter, Percy H. ^{[1
]}

Dhar, T. G. Murali ^{[1
]}

机构：

[1] Bristol Myers Squibb, Res & Dev, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb, Biocon Res Ctr, Bangalore, Karnataka, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 02期

关键词：

NUCLEAR RECEPTORS; GENE-EXPRESSION; DISCOVERY; POTENT; AUTOIMMUNE; MODULATORS; INTERLEUKIN-17; INHIBITION; PSORIASIS; DISEASE;

D O I：

10.1016/j.bmcl.2017.12.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：85 / 93

页数：9

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