title: Synthesis and structure-activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effects.
abstract: Recently we reported the adenine derivatives (2-4) as new interferon (IFN) inducers. In the present study, we conducted a detailed structure and activity relationship study of 4 and its related derivatives on IFN inducing activity. From this study, we found that compound 4 exhibited the most potent IFN inducing activity in vitro with a minimum effective concentration of 0.01 microM, and 4 also showed strong IFN-inducing activity at doses of more than 0.3mg/kg by oral administration in mice. This potency was 10-fold stronger than that of Imiquimod. Moreover, 4 did not cause emesis in ferrets even at doses as high as 10mg/kg, whereas, 80% of animals were emetic when orally administered with the same dose of Imiquimod. These results indicate that compound 4 is superior to Imiquimod with respect to efficacy and safety.
authors.affiliation: Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd., Konohana-ku, 554-0022, Osaka, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
authors.forename: Masanori
authors.initials: M
authors.lastname: Tobe
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Ogita
authors.forename: Ayumu
authors.initials: A
authors.lastname: Kurimoto
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Ogino
authors.forename: Hajime
authors.initials: H
authors.lastname: Kawakami
authors.forename: Haruo
authors.initials: H
authors.lastname: Takaku
authors.forename: Hironao
authors.initials: H
authors.lastname: Sajiki
authors.forename: Kosaku
authors.initials: K
authors.lastname: Hirota
authors.forename: Hideya
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000077271:Imiquimod; D007369:Interferon Inducers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000634:Aminoquinolines; D007369:Interferon Inducers; C002992:8-hydroxyadenine; D000225:Adenine; D000077271:Imiquimod