Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities.
In order to create novel compounds which possess potent interferon (IFN) inducing activities with excellent oral bioavailabilities, a series of 8-hydroxyadenines, which have various alkoxy or alkylthio moieties at the adenine C(2)-position, were synthesized and evaluated. The introduction of hydrophobic groups was not considered to be effective for potentiating the IFN-inducing activity, but several compounds having hydrophilic groups were effective. Among the compounds tested, compound 13f induced IFN from the dosage of 0.03 mg/kg, which was approximately 100-fold more potent than that of Imiquimod, and showed an excellent oral bioavailability (F=40%) which was 10-fold improved over 5, a lead compound (F=4%).
Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd., Konohana-ku, Osaka 554-0022, Japan. akurimot@sumitomopharm.co.jp
Ayumu
A
Kurimoto
Tetsuhiro
T
Ogino
Shinji
S
Ichii
Yoshiaki
Y
Isobe
Masanori
M
Tobe
Haruhisa
H
Ogita
Haruo
H
Takaku
Hironao
H
Sajiki
Kosaku
K
Hirota
Hajime
H
Kawakami
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006526:Hepatitis C / Q000188:drug therapy; D000077271:Imiquimod; D007372:Interferons / Q000032:analysis / Q000187:drug effects; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; C002992:8-hydroxyadenine; D007372:Interferons; D000225:Adenine; D000077271:Imiquimod