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Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-a]quinoxalin-4(5H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors

文献类型：期刊论文

作者Tian, Chaoquan3; Du, Husheng3; Sha, Wenjie3; Wu, Lingkang3; Yu, Zhixiao3; Song, Haoming3; Shen, Zihao3; Dai, Yan3; Li, Shuhui3; Mei, Wenyi3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-04-07
卷号68期号:8页码:8841-8860
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00439
英文摘要Bruton's tyrosine kinase (BTK) is a therapeutic target for B-cell-driven malignancies. Most of the approved covalent BTK inhibitors are associated with treatment limitations due to off-target toxicity and drug resistance. Developing noncovalent BTK inhibitors is a promising strategy to address unmet clinical needs. Here, a novel series of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives were designed and synthesized as noncovalent BTK inhibitors. Among them, representative compound 9 exhibited potent BTK inhibitory activity (IC50 = 21.6 nM) and excellent selectivity against a panel of 468 kinases. Moreover, the oral exposure property of compound 9 was improved, and the antitumor efficacy of compound 9 (TGI = 64.4%) was superior to the lead S2 (TGI = 28.7%) and Ibrutinib (TGI = 41.1%) in the U-937 xenograft models at an oral dosage of 50 mg/kg. All these results suggest that compound 9 is a potent, selective, and orally available noncovalent BTK inhibitor worthy of further development.
WOS关键词B-CELL ; IBRUTINIB ; IDENTIFICATION ; ACALABRUTINIB ; SNAPSHOT ; PK
资助项目National Natural Science Foundation of China[82425104] ; National Natural Science Foundation of China[81825020] ; National Natural Science Foundation of China[82150208] ; National Natural Science Foundation of China[2022YFC3400504] ; National Key Research and Development Program ; Fundamental Research Funds for the Central Universities ; National Program for Special Supports of Eminent Professionals ; National Program for Support of Top-notch Young Professionals
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001461009700001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/316950]  
专题新药研究国家重点实验室
通讯作者Diao, Yanyan; Jiang, Hualiang; Li, Honglin; Chen, Zhuo
作者单位1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.East China Normal Univ, Innovat Ctr AI & Drug Discovery, Sch Pharm, Shanghai 200062, Peoples R China
3.East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式
GB/T 7714		 Tian, Chaoquan,Du, Husheng,Sha, Wenjie,et al. Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-a]quinoxalin-4(5H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(8):8841-8860.
APA Tian, Chaoquan.,Du, Husheng.,Sha, Wenjie.,Wu, Lingkang.,Yu, Zhixiao.,...&Chen, Zhuo.(2025).Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-a]quinoxalin-4(5H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,68(8),8841-8860.
MLA Tian, Chaoquan,et al."Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-a]quinoxalin-4(5H)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 68.8(2025):8841-8860.

入库方式： OAI收割

来源：上海药物研究所

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