Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities

被引:76
作者
Kurimoto, A [1 ]
Ogino, T
Ichii, S
Isobe, Y
Tobe, M
Ogita, H
Takaku, H
Sajiki, H
Hirota, K
Kawakami, H
机构
[1] Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
[2] Gifu Pharmaceut Univ, Med Chem Lab, Gifu 5028585, Japan
关键词
8-hydroxyadenines; orally active; interferon inducer; HCV; imiquimod;
D O I
10.1016/j.bmc.2003.12.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1091 / 1099
页数:9
相关论文
共 36 条
[1]  
CHIRIGOS MA, 1992, THYMUS, V19, pS7
[2]   The scientific challenge of hepatitis C [J].
Cohen, J .
SCIENCE, 1999, 285 (5424) :26-30
[3]   Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C [J].
Davis, GL ;
Esteban-Mur, R ;
Rustgi, V ;
Hoefs, J ;
Gordon, SC ;
Trepo, C ;
Shiffman, ML ;
Zeuzem, S ;
Craxi, A ;
Ling, MH ;
Albrecht, J .
NEW ENGLAND JOURNAL OF MEDICINE, 1998, 339 (21) :1493-1499
[4]  
DIANZANI F, 1992, J INTERFERON RES, V12, P109
[5]   IMMUNOSTIMULANTS (REPRINTED FROM TRENDS IN PHARMACOLOGICAL SCIENCES, VOL 14, PG 169-174, 1993) [J].
HADDEN, JW .
IMMUNOLOGY TODAY, 1993, 14 (06) :275-280
[6]   Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway [J].
Hemmi, H ;
Kaisho, T ;
Takeuchi, O ;
Sato, S ;
Sanjo, H ;
Hoshino, K ;
Horiuchi, T ;
Tomizawa, H ;
Takeda, K ;
Akira, S .
NATURE IMMUNOLOGY, 2002, 3 (02) :196-200
[7]   Efficient synthesis of 2,9-disubstituted 8-hydroxyadenine derivatives [J].
Hirota, K ;
Kazaoka, K ;
Niimoto, I ;
Sajiki, H .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2003, 1 (08) :1354-1365
[8]   Discovery of 8-hydroxyadenines as a novel type of interferon inducer [J].
Hirota, K ;
Kazaoka, K ;
Niimoto, I ;
Kumihara, H ;
Sajiki, H ;
Isobe, Y ;
Takaku, H ;
Tobe, M ;
Ogita, H ;
Ogino, T ;
Ichii, S ;
Kurimoto, A ;
Kawakami, H .
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (25) :5419-5422
[9]   Synthesis and structure-activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effects [J].
Isobe, Y ;
Tobe, M ;
Ogita, H ;
Kurimoto, A ;
Ogino, T ;
Kawahami, H ;
Takaku, H ;
Sajiki, H ;
Hirota, K ;
Hayashi, H .
BIOORGANIC & MEDICINAL CHEMISTRY, 2003, 11 (17) :3641-3647
[10]  
ISTVAN A, 1999, ANTIVIR RES, V43, P55