A novel class of phosphonate nucleosides. 9-[(1-phosphonomethoxycyclopropyl)methyl]guanine as a potent and selective anti-HBV agent.
9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC(50) = 0.5 microM) 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 microM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 microM, pyrimidine analogues do not. 1 is 4 times more potent than 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), which was used as a positive control (EC(50) = 2.0 microM). 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.
Choi
Jong-Ryoo
JR
LG Life Sciences Ltd., R & D Park, 104-1 Moongi-dong, Yusung-gu, Daejeon 305-380, Korea. jrchoI@lgls.co.kr
Cho
Dong-Gyu
DG
Roh
Kee Y
KY
Hwang
Jae-Taeg
JT
Ahn
Sinbyoung
S
Jang
Hyun S
HS
Cho
Woo-Young
WY
Kim
Kyong W
KW
Cho
Young-Gyo
YG
Kim
Jeongmin
J
Kim
Yong-Zu
YZ
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D006147:Guanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006509:Hepatitis B / Q000188:drug therapy; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D008392:Marmota; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014162:Transfection
C487369:((1-((2-amino-9H-purin-9-yl)methyl)cyclopropyl)oxy)methylphosphonic acid dipivoxyl; C487368:9-((1-phosphonomethoxycyclopropyl)methyl)guanine; D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D006147:Guanine