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

Bioorg Med Chem Lett. 2009 Dec 15;19(24):6918-21. doi: 10.1016/j.bmcl.2009.10.072.

Peng Lu ¹, Jiangxia Liu, Yuya Wang, Xiaoyan Chen, Yushe Yang, Ruyun Ji

Affiliations

Affiliation

1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Science, Shanghai 201203, China.

PMID: 19889538 DOI: 10.1016/j.bmcl.2009.10.072

Abstract

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 IC(50) value of 0.12 microM, 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.

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