Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives

被引:23
作者
Bazin, Helene G. [1 ]
Li, Yufeng [1 ]
Khalaf, Juhienah K. [1 ]
Mwakwari, Sandra [1 ]
Livesay, Mark T. [1 ]
Evans, Jay T. [1 ]
Johnson, David A. [1 ]
机构
[1] GlaxoSmithKline Vaccines, Hamilton, MT 59840 USA
关键词
TLR7/8; agonist; Oxoadenine; Immunostimulants; POTENT INTERFERON INDUCERS; RECEPTOR; 7; AGONISTS; 8-OXOADENINE DERIVATIVES; BIOLOGICAL EVALUATION; TLR7; TOLL-LIKE-RECEPTOR-7; 8-HYDROXYADENINES; RESPONSES;
D O I
10.1016/j.bmcl.2015.01.037
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1318 / 1323
页数:6
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