Synthesis and structure-activity relationships of 2-amino-8-hydroxyadenines as orally active interferon inducing agents.
Recently, we have reported the 8-hydroxyadenine derivatives (2-4) as a novel class of interferon (IFN) inducing agents. In the present study, a series of 8-hydroxyadenines, which possess various amino moieties at the adenine C(2)-position, were synthesized and evaluated for their ability to induce endogenous IFN in comparison to the known active agent, Imiquimod. Among the compounds prepared, compound 9o possessing a 2-methoxyethylamino group at C(2)-position of adenine was found to exhibit potent IFN inducing activity in vivo. Compound 9o induced IFN from the dosage of 0.1 mg/kg, which was 30-fold potent than that of Imiquimod, and showed a good oral bioavailability (F=81%).
Kurimoto
Ayumu
A
Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co Ltd, Konohana-ku, Osaka 554-0022, Japan. akurimoto@sumitomopharm.co.jp
Ogino
Tetsuhiro
T
Ichii
Shinji
S
Isobe
Yoshiaki
Y
Tobe
Masanori
M
Ogita
Haruhisa
H
Takaku
Haruo
H
Sajiki
Hironao
H
Hirota
Kosaku
K
Kawakami
Hajime
H
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000284:Administration, Oral; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000077271:Imiquimod; D007369:Interferon Inducers / Q000138:chemical synthesis* / Q000494:pharmacology; D007372:Interferons / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D007369:Interferon Inducers; C002992:8-hydroxyadenine; D007372:Interferons; D000225:Adenine; D000077271:Imiquimod