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Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate

文献类型：期刊论文

作者Li, Daqiang2; Zhang, Zhuo2,4,5; Li, Yalei3; Wang, Xinyi3,5; Zhong, Hanyue2,5; Yang, Huajie2; Xi, Yong3; Liu, Hongchun3; Shen, Aijun1,3,5; Hu, Youhong2,4,5,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-05-15
卷号66期号:10页码:7016-7037
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00525
通讯作者Shen, Aijun(shenaj@simm.ac.cn) ; Hu, Youhong(yhhu@simm.ac.cn)
英文摘要A novel series of benzamide derivatives were successivelydesignedand synthesized prepared from the pyridazinone scaffold. Among them,(S)-17b, demonstrated potent inhibitoryactivity in vitro toward human class I HDAC isoformsand human myelodysplastic syndrome (SKM-1) cell line. Also, (S)-17b strongly increased the intracellularlevel of acetyl-histone H3 and P21 simultaneously and effectivelyinduced G1 cell cycle arrest and apoptosis. Through oral dosing inSKM-1 xenograft models, (S)-17b exhibitedexcellent in vivo antitumor activity. In addition,compound (S)-17b showed better antitumorefficacy on mouse models with intact immune system than those withthymus deficiencies. Furthermore, this compound displayed a favorablepharmacokinetic profile in ICR mice and SD rat, respectively, minimalmetabolic property differences among hepatocytes from five species,and a low inhibition upon the human ether-a-go-go (hERG) channel withan IC50 value of 34.6 mu M. This novel compound(S)-17b may serve as a new drug candidatefor further investigation.
WOS关键词HISTONE DEACETYLASE INHIBITORS ; HEPATITIS-B-VIRUS ; PYRIDAZINONE DERIVATIVES ; CANCER ; VORINOSTAT
资助项目Projects of the National Natural Science Foundation of China[22007094] ; Projects of the National Natural Science Foundation of China[82173831] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120215008] ; Shanghai Pujiang Program[2019PJD056] ; Science and Technology Commission of Shanghai Municipality[21ZR1475000]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001011413600001
源URL[http://119.78.100.183/handle/2S10ELR8/306284]  
专题新药研究国家重点实验室
通讯作者Shen, Aijun; Hu, Youhong
作者单位1.Lingang Lab, Shanghai 200031, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Univ Chinese Acad Sci, Beijing 110039, Peoples R China
6.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Li, Daqiang,Zhang, Zhuo,Li, Yalei,et al. Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(10):7016-7037.
APA Li, Daqiang.,Zhang, Zhuo.,Li, Yalei.,Wang, Xinyi.,Zhong, Hanyue.,...&Hu, Youhong.(2023).Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate.JOURNAL OF MEDICINAL CHEMISTRY,66(10),7016-7037.
MLA Li, Daqiang,et al."Discovery of (S)-N-(2-Amino-4-fluorophenyl)-4-(1-(3-(4-((dimethylamino)methyl)phenyl)-6-oxopyridazin-1(6H)-yl)ethyl)benzamide as Potent Class I Selective HDAC Inhibitor for Oral Anticancer Drug Candidate".JOURNAL OF MEDICINAL CHEMISTRY 66.10(2023):7016-7037.

入库方式： OAI收割

来源：上海药物研究所

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