Synthesis and structure-activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effects.
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.
Isobe
Yoshiaki
Y
Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd., Konohana-ku, 554-0022, Osaka, Japan.
Tobe
Masanori
M
Ogita
Haruhisa
H
Kurimoto
Ayumu
A
Ogino
Tetsuhiro
T
Kawakami
Hajime
H
Takaku
Haruo
H
Sajiki
Hironao
H
Hirota
Kosaku
K
Hayashi
Hideya
H
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
D000634:Aminoquinolines; D007369:Interferon Inducers; C002992:8-hydroxyadenine; D000225:Adenine; D000077271:Imiquimod