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Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity

文献类型：期刊论文

作者Sun, Nannan1,3,4; Yu, Mingcheng4; Jiang, Zhengyuan4; Yang, Feng2,4; Lu, Lixue4; Xia, Yuehan4; Zhao, Yunpeng4; Huang, Yafei4; Chen, Song4; Chen, Shijie2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-05-05
卷号251页码:115213
关键词ROR?t agonists Carbazole carboxamide Agonistic activity Metabolic stability Co-crystallization Molecular docking
DOI10.1016/j.ejmech.2023.115213
文献子类Article
英文摘要Based on two previously discovered carbazole carboxamide retinoic acid receptor-related orphan receptor-gamma t (ROR gamma t) agonists 6 and 7 (t1/2 = 8.7 min and 16.4 min in mouse liver microsome, respectively), new carbazole carboxamides were designed and synthesized according to the molecular mechanism of action (MOA) and metabolic site analysis with the aim of identifying novel ROR gamma t agonists with optimal pharmacological and metabolic profiles. By modifying the agonist lock touching substitutions on carbazole ring, introducing het-eroatoms into different parts of the molecule and attaching a side chain to the sulfonyl benzyl moiety, several potent ROR gamma t agonists were identified with greatly improved metabolic stability. Best overall properties were achieved in compound (R) -10f with high agonistic activities in ROR gamma t dual FRET (EC50 = 15.6 nM) and Gal4 reporter gene (EC50 = 141 nM) assays and greatly improved metabolic stability (t1/2 > 145 min) in mouse liver microsome. Besides, the binding modes of (R) -10f and (S) -10f in ROR gamma t ligand binding domain (LBD) were also studied. Altogether, the optimization of carbazole carboxamides led to the discovery of (R) -10f as a potential small molecule therapeutics for cancer immunotherapy.
WOS关键词GAMMA-T AGONISTS ; NUCLEAR RECEPTOR ; DISCOVERY
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000951597600001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/309676]  
专题新药研究国家重点实验室
通讯作者Wang, Yonghui; Xie, Qiong
作者单位1.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, 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;
4.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Sun, Nannan,Yu, Mingcheng,Jiang, Zhengyuan,et al. Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,251:115213.
APA Sun, Nannan.,Yu, Mingcheng.,Jiang, Zhengyuan.,Yang, Feng.,Lu, Lixue.,...&Xie, Qiong.(2023).Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,251,115213.
MLA Sun, Nannan,et al."Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 251(2023):115213.

入库方式： OAI收割

来源：上海药物研究所

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