Prodrugs of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine: potent interferon inducing agents in monkeys.
In order to improve the oral bioavailability of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine (SM-295072), a potent interferon (IFN) inducing agent, we synthesized prodrugs of it by utilizing the hydroxy groups at the C(2)-side chain and/or the C(8)-position. The carbonate prodrug at the C(8)-position was more effective than that at the C(2)-side chain for oral absorption in rats. Among the compounds prepared, compound 6 demonstrated the most preferable prodrug properties, and the maximum plasma concentration of 6 was approximately 4-fold higher than that of SM-295072. Furthermore, compound 6 was dose-dependently absorbed in monkeys by oral administration, and exhibited a potent IFN-inducting activity that correlated well with its plasma drug concentration.
Kurimoto
Ayumu
A
Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd, Naka, Osaka, Japan.
Tobe
Masanori
M
Ogita
Haruhisa
H
Ogino
Tetsuhiro
T
Takaku
Haruo
H
Ichii
Shinji
S
Kawakami
Hajime
H
Isobe
Yoshiaki
Y
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D007369:Interferon Inducers / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007372:Interferons / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
C493037:9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine; D007369:Interferon Inducers; D011355:Prodrugs; D007372:Interferons; D000225:Adenine