We report the synthesis and biological evaluation of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety. In vitro evaluation of the piperidinyl-substituted oxoadenines 3a-g in human TLR7- or TLR8-transfected HEK293 cells and in human PBMCs indicated that TLR7/8 selectivity/potency and cytokine induction can be modulated by varying the length of the alkyl linker. Oxoadenine 3f containing a 5-carbon linker was found to be the most potent TLR7 agonist and IFN alpha inducer in the series whereas 3b possessing a 1-carbon linker was the most potent TLR8 agonist. (C) 2015 Elsevier Ltd. All rights reserved.
机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Isobe, Y
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Tobe, M
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Tobe, M
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Ogita, H
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Ogita, H
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Kurimoto, A
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Kurimoto, A
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Ogino, T
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Ogino, T
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Kawahami, H
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Kawahami, H
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Takaku, H
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Takaku, H
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Sajiki, H
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Hirota, K
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Hirota, K
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Hayashi, H
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Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, JapanSumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Isobe, Y
;
Tobe, M
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Tobe, M
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Ogita, H
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Ogita, H
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Kurimoto, A
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Kurimoto, A
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Ogino, T
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Ogino, T
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Kawahami, H
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Kawahami, H
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Takaku, H
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Takaku, H
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Sajiki, H
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Hirota, K
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机构:Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan
Hirota, K
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Hayashi, H
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Sumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, JapanSumitomo Pharmaceut Co Ltd, Discovery Res Labs 2, Div Res, Konohana Ku, Osaka 5540022, Japan