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

被引：24

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 06期

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

页码：1318 / 1323

页数：6

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