Evaluation of anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]- guanine (A-5021) in mice.
The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guani ne (A-5021) was evaluated in murine cells and in several murine models of herpes simplex virus (HSV) infection. Against HSV type 1 (HSV-1), A-5021 was 15-30- and 30-60-fold more active, and against HSV type 2 (HSV-2), it was 2- and 8-fold more active than acyclovir and penciclovir in Balb/3T3 cells, respectively. When antiviral compounds were administered orally (once daily) to mice infected intraperitoneally with HSV-1 (Tomioka), A-5021 was more active than acyclovir or famciclovir in spite of its relatively low oral bioavailability. A-5021 was as active as penciclovir when the antiviral compounds were given intravenously (three times daily) to mice infected intraperitoneally with HSV-2 (186). In mice with a cutaneous HSV-1 (KOS) infection, three times daily oral therapy with A-5021 at 25 mg/kg per day produced more significant reduction in severity of skin lesions than equivalent treatment with acyclovir or famciclovir. In mice infected intracerebrally with HSV-1 (Tomioka), complete survival was observed in the group treated intravenously with A-5021 at 25 mg/kg per day (three times daily), while more than 50% of mice died in the groups treated intravenously with acyclovir of up to 100 mg/kg per day (three times daily). Moreover, A-5021 was more effective than acyclovir in clearing infectious virus from the brain. These findings demonstrate that A-5021 has potent anti-HSV activity in several murine models.
Iwayama
S
S
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan.
Ohmura
Y
Y
Suzuki
K
K
Ono
N
N
Nakazawa
H
H
Aoki
M
M
Tanabe
I
I
Sekiyama
T
T
Tsuji
T
T
Okunishi
M
M
Yamanishi
K
K
Nishiyama
Y
Y
D016475:3T3 Cells; D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004195:Disease Models, Animal; D004341:Drug Evaluation; D004660:Encephalitis / Q000188:drug therapy / Q000821:virology; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006561:Herpes Simplex / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010537:Peritoneum / Q000187:drug effects / Q000473:pathology / Q000821:virology; D018139:Simplexvirus / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000821:virology; D015996:Survival Rate
C111645:9-((cis-1,2-bis(hydroxymethyl)cycloprop-1-yl)methyl)guanine; D000998:Antiviral Agents; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir