Sun Nannan, Yu Mingcheng, Jiang Zhengyuan, Yang Feng, Lu Lixue, Xia Yuehan, Zhao Yunpeng, Huang Yafei, Chen Song, Chen Shijie, Luo Cheng, Wang Yonghui, Xie Qiong
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China; Fudan Zhangjiang Institute, Shanghai, 201203, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai, 201203, China.
Eur J Med Chem. 2023 May 5;251:115213. doi: 10.1016/j.ejmech.2023.115213. Epub 2023 Mar 2.
Based on two previously discovered carbazole carboxamide retinoic acid receptor-related orphan receptor-γt (RORγt) agonists 6 and 7 (t = 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 RORγt agonists with optimal pharmacological and metabolic profiles. By modifying the "agonist lock" touching substitutions on carbazole ring, introducing heteroatoms into different parts of the molecule and attaching a side chain to the sulfonyl benzyl moiety, several potent RORγt agonists were identified with greatly improved metabolic stability. Best overall properties were achieved in compound (R)-10f with high agonistic activities in RORγt dual FRET (EC = 15.6 nM) and Gal4 reporter gene (EC = 141 nM) assays and greatly improved metabolic stability (t > 145 min) in mouse liver microsome. Besides, the binding modes of (R)-10f and (S)-10f in RORγt 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.
基于之前发现的两种咔唑甲酰胺维甲酸受体相关孤儿受体-γt（RORγt）激动剂6和7（在小鼠肝微粒体中的t分别为8.7分钟和16.4分钟），根据作用分子机制（MOA）和代谢位点分析设计并合成了新的咔唑甲酰胺，旨在鉴定具有最佳药理和代谢特性的新型RORγt激动剂。通过修饰咔唑环上的“激动剂锁定”接触取代基，在分子的不同部位引入杂原子，并在磺酰苄基部分连接侧链，鉴定出了几种具有显著提高的代谢稳定性的强效RORγt激动剂。化合物（R）-10f在RORγt双荧光共振能量转移（EC = 15.6 nM）和Gal4报告基因（EC = 141 nM）测定中具有高激动活性，并且在小鼠肝微粒体中的代谢稳定性大大提高（t > 145分钟），从而实现了最佳的整体性能。此外，还研究了（R）-10f和（S）-10f在RORγt配体结合结构域（LBD）中的结合模式。总之，咔唑甲酰胺的优化导致发现了（R）-10f作为癌症免疫治疗的潜在小分子疗法。
