A novel class of phosphonate nucleosides. 9-[(1-phosphonomethoxycyclopropyl)methyl]guanine as a potent and selective anti-HBV agent

被引：61

作者：

Choi, JR ^{[1
]}

Cho, DG ^{[1
]}

Roh, KY ^{[1
]}

Hwang, JT ^{[1
]}

Ahn, S ^{[1
]}

Jang, HS ^{[1
]}

Cho, WY ^{[1
]}

Kim, KW ^{[1
]}

Cho, YG ^{[1
]}

Kim, J ^{[1
]}

Kim, YZ ^{[1
]}

机构：

[1] LG Life Sci Ltd, Taejon 305380, South Korea

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 11期

关键词：

D O I：

10.1021/jm0305265

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC50 = 0.5 muM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 muM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 muM, pyrimidine analogues do not. 1 is 4 times more potent than 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA), which was used as a positive control (EC50 = 2.0 muM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.

引用

页码：2864 / 2869

页数：6

共 29 条

[1] MARKED INVIVO ANTIRETROVIRUS ACTIVITY OF 9-(2-PHOSPHONYLMETHOXY-ETHYL)ADENINE, A SELECTIVE ANTI-HUMAN IMMUNODEFICIENCY VIRUS AGENT [J].