Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

被引：10

作者：

Chen, Lei ^{[1
,2
]}

Su, Mei ^{[3
]}

Jin, Qiu ^{[3
]}

Wang, Wei ^{[3
]}

Wang, Chun-Gu ^{[1
,2
]}

Assani, Israa ^{[1
,2
]}

Wang, Mu-Xuan ^{[1
,2
]}

Zhao, Shi-Feng ^{[1
,2
]}

Lv, Shen-Min ^{[1
,2
]}

Wang, Jia-Wei ^{[1
,2
]}

Sun, Bo ^{[1
,2
]}

Li, Yan ^{[1
,2
]}

Liao, Zhi-Xin ^{[1
,2
]}

机构：

[1] Southeast Univ, Sch Chem & Chem Engn, Dept Pharmaceut Engn, Nanjing 211189, Peoples R China

[2] Southeast Univ, Jiangsu Prov Hitech Key Lab Biomed Res, Nanjing 211189, Peoples R China

[3] Jiangsu Carefree Pharmaceut Co Ltd, Nanjing 210042, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 21期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

ROR-GAMMA; SKIN INFLAMMATION; PSORIASIS; INTERLEUKIN-17; PATHWAY; IL-17;

D O I：

10.1021/acs.jmedchem.1c01436

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. ROR gamma t is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8(+) T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel ROR gamma t inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

引用

页码：16106 / 16131

页数：26

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