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1.
J Med Chem ; 53(7): 2964-72, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-20232824

ABSTRACT

Systemic administration of a Toll-like receptor 7 (TLR7) agonist is effective to in suppressing Th2 derived inflammation, however systemic induction of various cytokines such as IL-6, IL-12, and type I interferon (IFN) is observed. This cytokine induction would be expected to cause flu-like symptoms. We have previously reported adenine compounds (3, 4) as interferon inducing agents acting as TLR7 agonists. To identify potent anti-inflammatory compounds without systemic side effects, a labile carboxylic ester as an antedrug functionality onto the N(9)-benzyl group of the adenine was introduced. We found that 9e was a potent TLR7 agonist (EC(50) 50 nM) and rapidly metabolized by human plasma (T(1/2) 2.6 min) to the pharmacologically much less active carboxylic acid 16. Intratracheal administration of 9e effectively inhibited allergen-induced airway inflammation without inducing cytokines systemically. Therefore, the TLR7 agonist with antedrug characteristics 9e (SM-324405) is a novel candidate for immunotherapy of allergic diseases.


Subject(s)
Adenine/analogs & derivatives , Toll-Like Receptor 7/agonists , Adenine/adverse effects , Adenine/chemical synthesis , Adenine/pharmacology , Adenine/therapeutic use , Animals , Carboxylic Acids/chemistry , Cell Line , Drug Stability , Humans , Hypersensitivity/metabolism , Hypersensitivity/therapy , Immunotherapy , Inflammation/drug therapy , Inflammation/metabolism , Interferons/biosynthesis , Male , Rats , Toll-Like Receptor 7/metabolism
2.
J Med Chem ; 49(6): 2088-95, 2006 Mar 23.
Article in English | MEDLINE | ID: mdl-16539397

ABSTRACT

Recently we reported the adenine derivatives 3a-d as novel interferon (IFN) inducers. In the present study, we conducted a detailed structure-activity relationship study of analogues of 3a-d with respect to their IFN-inducing activity, mainly focusing on the N(9)-position of the adenine. From this study, we found that introduction of the 3-pyridylmethyl moiety was effective to increase in vitro activity, and compound 9ae was identified as being the most potent IFN inducer. This compound gave a minimum effective concentration (MEC) of 3 nM, which is comparable with that of R-848, a second generation IFN inducer. Compound 9ae also demonstrated potent IFN-inducing activity at a dose of 0.1 mg/kg by oral administration in mice. Furthermore, compound 9ae induced IFN in monkeys in a dose dependent manner, with a potency superior to that of R-848. In addition, 9ae did not cause emesis in ferrets even at a dose of 30 mg/kg. In this study the maximum plasma concentration of 9ae was 1019 ng/mL (ca. 3.1 microM), which was approximately 1000-fold higher than the MEC value. Therefore, with respect to both the efficacy and the safety margin, compound 9ae (SM-276001) is considered to be a promising compound as an orally active IFN inducer.


Subject(s)
Adenine/analogs & derivatives , Adenine/chemical synthesis , Interferon Inducers/chemical synthesis , Pyridines/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Administration, Oral , Animals , Ferrets , In Vitro Techniques , Interferon Inducers/pharmacology , Interferons/biosynthesis , Macaca fascicularis , Male , Mice , Pyridines/chemistry , Pyridines/pharmacology , Spleen/cytology , Spleen/drug effects , Spleen/metabolism , Structure-Activity Relationship , Vomiting/chemically induced
3.
Chem Pharm Bull (Tokyo) ; 52(4): 466-9, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15056968

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-Dawley
4.
Bioorg Med Chem ; 12(5): 1091-9, 2004 Mar 01.
Article in English | MEDLINE | ID: mdl-14980621

ABSTRACT

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 Relationship
5.
Bioorg Med Chem ; 11(24): 5501-8, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14642594

ABSTRACT

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 Relationship
6.
Bioorg Med Chem ; 11(17): 3641-7, 2003 Aug 15.
Article in English | MEDLINE | ID: mdl-12901909

ABSTRACT

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.


Subject(s)
Adenine/analogs & derivatives , Interferon Inducers/chemistry , Interferon Inducers/pharmacology , Adenine/chemistry , Adenine/pharmacology , Administration, Oral , Aminoquinolines/pharmacology , Animals , Imiquimod , Interferon Inducers/chemical synthesis , Interferon Inducers/toxicity , Mice , Mice, Inbred BALB C , Spleen/cytology , Structure-Activity Relationship , Vomiting/chemically induced
7.
J Med Chem ; 45(25): 5419-22, 2002 Dec 05.
Article in English | MEDLINE | ID: mdl-12459008

ABSTRACT

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.


Subject(s)
Adenine/analogs & derivatives , Adenine/chemical synthesis , Interferon Inducers/chemical synthesis , Adenine/pharmacology , Administration, Oral , Animals , In Vitro Techniques , Interferon Inducers/pharmacology , Mice , Spleen/cytology , Structure-Activity Relationship
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