ABSTRACT
In order to improve the oral bioavailability of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine (SM-295072), a potent interferon (IFN) inducing agent, we synthesized prodrugs of it by utilizing the hydroxy groups at the C(2)-side chain and/or the C(8)-position. The carbonate prodrug at the C(8)-position was more effective than that at the C(2)-side chain for oral absorption in rats. Among the compounds prepared, compound 6 demonstrated the most preferable prodrug properties, and the maximum plasma concentration of 6 was approximately 4-fold higher than that of SM-295072. Furthermore, compound 6 was dose-dependently absorbed in monkeys by oral administration, and exhibited a potent IFN-inducting activity that correlated well with its plasma drug concentration.
Subject(s)
Adenine/analogs & derivatives , Adenine/pharmacokinetics , Interferon Inducers/pharmacokinetics , Prodrugs/pharmacokinetics , Adenine/chemical synthesis , Animals , Area Under Curve , Caco-2 Cells , Chromatography, High Pressure Liquid , Half-Life , Humans , Hydroxylation , Interferon Inducers/chemical synthesis , Interferons/metabolism , Macaca fascicularis , Male , Prodrugs/chemical synthesis , Rats , Rats, Sprague-DawleyABSTRACT
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%).
Subject(s)
Adenine , Adenine/analogs & derivatives , Adenine/pharmacokinetics , Adenine/chemical synthesis , Adenine/pharmacology , Administration, Oral , Aminoquinolines/pharmacology , Animals , Biological Availability , Cells, Cultured , Dose-Response Relationship, Drug , Hepatitis C/drug therapy , Imiquimod , Interferons/analysis , Interferons/drug effects , Mice , Rats , Structure-Activity RelationshipABSTRACT
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%).
Subject(s)
Adenine/analogs & derivatives , Adenine/chemical synthesis , Interferon Inducers/chemical synthesis , Interferons/biosynthesis , Adenine/pharmacology , Administration, Oral , Aminoquinolines/pharmacology , Animals , Imiquimod , Interferon Inducers/pharmacology , Interferons/analysis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Molecular Structure , Spleen/cytology , Spleen/metabolism , Structure-Activity RelationshipABSTRACT
9-Benzyl-8-hydroxyadenine (6) was found to possess interferon-inducing activity in vitro as a lead compound. Although replacement of the 9-benzyl group of 6 did not improve the activity, the introduction of a substituent such as alkyl, alkylthio, alkylamino, and alkoxy groups into the 2-position of the adenine ring resulted in a remarkable increase in the activity. The 2-alkylthio (30-32), 2-butylamino (41), and 2-butoxy (47) analogues indicated the highest activities by oral administration to mice.
