title: Prodrugs of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine: potent interferon inducing agents in monkeys.
abstract: 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.
authors.affiliation: Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd, Naka, Osaka, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Kurimoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Tobe
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Ogita
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Ogino
authors.forename: Haruo
authors.initials: H
authors.lastname: Takaku
authors.forename: Shinji
authors.initials: S
authors.lastname: Ichii
authors.forename: Hajime
authors.initials: H
authors.lastname: Kawakami
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
mesh_terms: 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
chemical_list: C493037:9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine; D007369:Interferon Inducers; D011355:Prodrugs; D007372:Interferons; D000225:Adenine