Structural optimization of phthalazine derivatives for anti-HBV activities to improve oral bioavailability
文献类型：期刊论文
| 作者 | Yang, Yurong3,6; Xiao, Fuling4,5,6; Zuo, Jianping4,5,6 ; Yang, Li4,5,6; Hu, Youhong1,2,3,4,6; Chen, Wuhong6
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
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| 出版日期 | 2025-10-01 |
| 卷号 | 128页码:10 |
| 关键词 | HBV Capsid assembly modulators Structural optimization Oxidative metabolism |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2025.118259 |
| 英文摘要 | The hepatitis B virus (HBV) capsid protein forms a protective nucleocapsid essential for viral replication, establishing capsid assembly modulation as a promising therapeutic strategy. Based on previous mechanistic studies, we identified phthalazine derivatives as potent HBV capsid assembly modulators (CAMs), with Yhhu6517 exhibiting submicromolar antiviral activity in vitro. However, its clinical translation was hindered by poor oral pharmacokinetics (PK), due to rapid first-pass metabolism of oxidation-prone primary alcohol groups. Through metabolic stability-guided structure-activity relationship (SAR) studies involving systematic replacement of primary alcohols with non-primary alcohol-derived hydrophilic groups, we optimized the fragments to yield compound 2p. This optimized candidate 2p maintained a potent anti-HBV activity (IC50 = 0.016 mu M in HepG2.2.15 cells) while demonstrating improved an oral bioavailability (F = 80.6 % in mice) and enhanced plasma exposure (AUC0-24h = 10.3 mu g & sdot;h/mL). These findings confirm phthalazine-based anti-HBV agents, with compound 2p emerging as a candidate for the further development. |
| WOS关键词 | HEPATITIS-B-VIRUS ; MANAGEMENT ; INHIBITORS |
| 资助项目 | National Natural Science Foundation of P. R. China[82104240] ; National Science and Technology Major Project[2018ZX09711002-014-004] ; Shanghai Science and Technology Innovation Project[20S11906200] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001502502100001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318246]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Li; Hu, Youhong; Chen, Wuhong |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1st Xiangshan Branch Alley, Hangzhou 310024, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Xianlin Rd 138, Nanjing 210023, Peoples R China 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Immunol Dis Res Ctr, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yang, Yurong,Xiao, Fuling,Zuo, Jianping,et al. Structural optimization of phthalazine derivatives for anti-HBV activities to improve oral bioavailability[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2025,128:10. |
| APA | Yang, Yurong,Xiao, Fuling,Zuo, Jianping,Yang, Li,Hu, Youhong,&Chen, Wuhong.(2025).Structural optimization of phthalazine derivatives for anti-HBV activities to improve oral bioavailability.BIOORGANIC & MEDICINAL CHEMISTRY,128,10. |
| MLA | Yang, Yurong,et al."Structural optimization of phthalazine derivatives for anti-HBV activities to improve oral bioavailability".BIOORGANIC & MEDICINAL CHEMISTRY 128(2025):10. |
入库方式： OAI收割
来源：上海药物研究所
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