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%). (C) 2003 Elsevier Ltd. All rights reserved.