Design, synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) as potent HBV inhibitors

doi:10.1016/j.bmcl.2009.10.072

	Design, synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) as potent HBV inhibitors
	Lu, Peng 1; Liu, Jiangxia 2; Wang, Yuya 1; Chen, Xiaoyan1 ; Yang, Yushe1 ; Ji, Ruyun 1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2009-12-15
卷号	19 期号:24 页码:6918-6921
关键词	Oxazaphosphorine Prodrug Hepatitis B virus
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2009.10.072
文献子类	Article
英文摘要	A series of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) were synthesized and their anti-hepatitis B virus (HBV) activity was evaluated in HepG2 2.2.15 cells, with adefovir dipivoxil as a reference drug. In the cell assays, compounds 7b and 7d exhibited anti-HBV activity comparable to that of adefovir dipivoxil, while compound 7c, with an IC50 value of 0.12 mu M, was found to be three times more potent than the reference compound. In vitro stability studies showed that (S-P,S)-7c, the diastereomer of compound 7c, was stable in human blood plasma but underwent rapid metabolism to release the parent drug PMEA in liver microsomes. The possible metabolic pathway of (S-P,S)-7c in human liver microsomes was described. These findings suggest that compound (S-P,S)-7c is a promising anti-HBV drug candidate for further development. (C) 2009 Elsevier Ltd. All rights reserved.
WOS关键词	CHRONIC HEPATITIS-B ; INTRACELLULAR DELIVERY ; HYDROXAMIC ACIDS ; VIRUS-INFECTION ; DERIVATIVES ; CELLS ; 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE ; 5'-MONOPHOSPHATE ; PHOSPHONATES ; NUCLEOTIDES
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000271724200020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279063]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Yang, Yushe
作者单位	1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China; 2.Fudan Univ, Key Lab Med Mol Viol, Inst Med Microbiol, Shanghai Med Coll, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	Lu, Peng,Liu, Jiangxia,Wang, Yuya,et al. Design, synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) as potent HBV inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2009,19(24):6918-6921.
APA	Lu, Peng,Liu, Jiangxia,Wang, Yuya,Chen, Xiaoyan,Yang, Yushe,&Ji, Ruyun.(2009).Design, synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) as potent HBV inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,19(24),6918-6921.
MLA	Lu, Peng,et al."Design, synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) as potent HBV inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 19.24(2009):6918-6921.