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Design, synthesis and biological evaluation of chalcone derivatives as potent and orally active hCYP3A4 inhibitors

文献类型：期刊论文

作者Lu, Shiwei3,4,5; Zhang, Feng5; Gong, Jiahao5; Huang, Jian2; Zhu, Guanghao5; Zhao, Yitian3,4,5; Jia, Qi5; Li, Yiming5; Li, Bo1,3,4; Chen, Kaixian1,3,4,5
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2023-10-15
卷号95页码:9
ISSN号0960-894X
关键词Cytochrome P450 3A4 (CYP3A4) Inhibitors Isoquinoline chalcones Orally active
DOI10.1016/j.bmcl.2023.129435
通讯作者Li, Bo(boli@simm.ac.cngegu) ; Zhu, Weiliang(wlzhu@simm.ac.cn) ; Ge, Guangbo(geguangbo@shutcm.edu.cn)
英文摘要Human cytochrome P450 3A4 (hCYP3A4), one of the most important drug-metabolizing enzymes, catalyze the metabolic clearance of similar to 50% therapeutic drugs. CYP3A4 inhibitors have been used for improving the in vivo efficacy of hCYP3A4-substrate drugs. However, most of existing hCYP3A4 inhibitors may trigger serious adverse effects or undesirable effects on endogenous metabolism. This study aimed to discover potent and orally active hCYP3A4 inhibitors from chalcone derivatives and to test their anti-hCYP3A4 effects both in vitro and in vivo. Following three rounds of screening and structural optimization, the isoquinoline chalcones were found with excellently anti-hCYP3A4 effects. SAR studies showed that introducing an isoquinoline ring on the A-ring significantly enhanced anti-CYP3A4 effect, generating A10 (IC50 = 102.10 nM) as a promising lead compound. The 2nd round of SAR studies showed that introducing a substituent group at the para position of the carbonyl group on B-ring strongly improved the anti-CYP3A4 effect. As a result, C6 was identified as the most potent hCYP3A4 inhibitor (IC50 = 43.93 nM) in human liver microsomes (HLMs). C6 also displayed potent antihCYP3A4 effect in living cells (IC50 = 153.00 nM), which was superior to the positive inhibitor ketoconazole (IC50 = 251.00 nM). Mechanistic studies revealed that C6 could potently inhibit CYP3A4-catalyzed N-ethyl-1,8naphthalimide (NEN) hydroxylation in a competitive manner (Ki = 30.00 nM). Moreover, C6 exhibited suitable metabolic stability in HLMs and showed good safety profiles in mice. In vivo tests demonstrated that C6 (100 mg/ kg, orally administration) significantly increased the AUC(0-inf) of midazolam by 3.63-fold, and strongly prolonged its half-life by 1.66-fold compared with the vehicle group in mice. Collectively, our findings revealed the SARs of chalcone derivatives as hCYP3A4 inhibitors and offered several potent chalcone-type hCYP3A4 inhibitors, while C6 could serve as a good lead compound for developing novel, orally active CYP3A4 inhibitors with improved druglikeness properties.
WOS关键词DRUG-DRUG INTERACTIONS ; CYTOCHROME-P450 ENZYMES ; MOLECULAR DOCKING ; ANTIBACTERIAL ; METABOLISM
资助项目Chinese Pharmaceutical Association-Yiling Biopharmaceutical Innovation Project[CPAYLJ201908] ; National Key Research and Development Program of China[2022YFA1004304] ; National Natural Science Foundation of China[22277129] ; National Natural Science Foundation of China[81922070] ; National Natural Science Foundation of China[82273897] ; National Natural Science Foundation of China[22077131] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004] ; Shanghai Municipal Health Commission's TCM research project[2022CX005] ; State Key Laboratory of Fine Chemicals, Dalian University of Technology[KF2022] ; Three-year Action Plan for Shanghai TCM Development and Inheritance Program[ZY (2021-2023)-0401]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号WOS:001080787100001
源URL[http://119.78.100.183/handle/2S10ELR8/307394]  
专题新药研究国家重点实验室
通讯作者Li, Bo; Zhu, Weiliang; Ge, Guangbo
作者单位1.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Shanghai Inst Food & Drug Control, Pharmacol & Toxicol Div, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
5.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Sch Pharm, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Shiwei,Zhang, Feng,Gong, Jiahao,et al. Design, synthesis and biological evaluation of chalcone derivatives as potent and orally active hCYP3A4 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2023,95:9.
APA Lu, Shiwei.,Zhang, Feng.,Gong, Jiahao.,Huang, Jian.,Zhu, Guanghao.,...&Ge, Guangbo.(2023).Design, synthesis and biological evaluation of chalcone derivatives as potent and orally active hCYP3A4 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,95,9.
MLA Lu, Shiwei,et al."Design, synthesis and biological evaluation of chalcone derivatives as potent and orally active hCYP3A4 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 95(2023):9.

入库方式： OAI收割

来源：上海药物研究所

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