Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) inverse agonists
文献类型：期刊论文
| 作者 | Lu, Lixue1; Chen, Song1; Yu, Mingcheng1; Zhou, Ronghui1; Guo, Siqi2; Chen, Ji-an1; Wang, Haojie1; Chen, Shijie2; Luo, Cheng2 ; Xie, Qiong1,3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-08-05 |
| 卷号 | 256页码:18 |
| ISSN号 | 0223-5234 |
| 关键词 | ROR gamma t Triazines Inverse agonist Psoriasis Autoimmune diseases |
| DOI | 10.1016/j.ejmech.2023.115424 |
| 通讯作者 | Xie, Qiong(qxie@fudan.edu.cn) ; Wang, Yonghui(yonghuiwang@fudan.edu.cn) |
| 英文摘要 | Retinoic Acid Receptor-Related Orphan Receptor gamma t (ROR gamma t) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel ROR gamma t inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak ROR gamma t inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent ROR gamma t inverse agonists with IC50 values in the range of 7 nM-50 nM in ROR gamma t dual FRET assay. Among them, compound 14g displayed potent ROR gamma t inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 mu M and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0- Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazinebased derivatives represent a new chemical class of ROR gamma t inverse agonists as potential therapeutic agents against autoimmune diseases. |
| WOS关键词 | DIFFERENTIATION ; INTERLEUKIN-17A ; SECUKINUMAB ; PSORIASIS ; AMIDES ; PHASE ; CELLS |
| 资助项目 | National Natural Science Foundation of China[81973163] ; National Natural Science Foundation of China[81874287] ; Shanghai Bio- pharmaceutical Science and Technology Supporting Plan[19431900100] ; Natural Science Foundation of Shanghai[19ZR1436700] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:001007650800001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306343]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xie, Qiong; Wang, Yonghui |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Fudan Zhangjiang Inst, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lu, Lixue,Chen, Song,Yu, Mingcheng,et al. Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) inverse agonists[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,256:18. |
| APA | Lu, Lixue.,Chen, Song.,Yu, Mingcheng.,Zhou, Ronghui.,Guo, Siqi.,...&Wang, Yonghui.(2023).Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) inverse agonists.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,256,18. |
| MLA | Lu, Lixue,et al."Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) inverse agonists".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 256(2023):18. |
入库方式： OAI收割
来源：上海药物研究所
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