Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity.
Optimization of carbazole carboxamide RORγt agonists: Challenges in improving the metabolic stability and maintaining the agonistic activity.
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DOI：
10.1016/j.ejmech.2023.115213
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发表时间：
2023-03
影响因子：
6.7
通讯作者：
Nan-nan Sun;Ming-cheng Yu;Zhen-xiu Jiang;Fengling Yang;Lixue Lu;Yuehan Xia;Yunpeng Zhao;Yafei Huang;Song Chen;Shijie Chen;Cheng Luo;Yonghui Wang;Qiong Xie
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文献类型：
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作者：
Nan-nan Sun;Ming-cheng Yu;Zhen-xiu Jiang;Fengling Yang;Lixue Lu;Yuehan Xia;Yunpeng Zhao;Yafei Huang;Song Chen;Shijie Chen;Cheng Luo;Yonghui Wang;Qiong Xie
基于先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（t1/2分别为8.7 min和16.4 min），根据分子作用机制和代谢位点分析，设计并合成了新的咔唑酰胺类化合物，旨在筛选具有最佳药理学和代谢特性的新型RORγt激动剂。通过修饰咔唑环上的“激动剂锁”接触取代，在分子的不同部分引入杂原子并将侧链连接到磺酰基苄基部分，鉴定出几种有效的RORγt激动剂，其代谢稳定性大大改善。化合物（R）-10 f在RORγt双重FRET（EC 50 = 15.6 nM）和Gal 4报告基因（EC 50 = 141 nM）测定中具有高激动活性，并且在小鼠肝微粒体中大大改善了代谢稳定性（t1/2> 145 min），从而实现了最佳的总体性质。此外，还研究了（R）-10f和（S）-10fin RORγt配体结合域（LBD）的结合模式。总之，咔唑甲酰胺的优化导致发现（R）-10fa作为用于癌症免疫疗法的潜在小分子疗法。
Based on two previously discovered carbazole carboxamide retinoic acid receptor-related orphan receptor-γt (RORγt) agonists6and7(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 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)-10fwith high agonistic activities in RORγt 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)-10fand (S)-10fin RORγt ligand binding domain (LBD) were also studied. Altogether, the optimization of carbazole carboxamides led to the discovery of (R)-10fas a potential small molecule therapeutics for cancer immunotherapy.