The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics

被引：24

作者：

Bazin, Helene G. ^{[1
]}

Murray, Tim J. ^{[1
]}

Bowen, William S. ^{[1
]}

Mozaffarian, Afsaneh ^{[1
]}

Fling, Steven P. ^{[1
]}

Bess, Laura S. ^{[1
]}

Livesay, Mark T. ^{[1
]}

Arnold, Jeffrey S. ^{[1
]}

Johnson, Craig L. ^{[1
]}

Ryter, Kendal T. ^{[1
]}

Cluff, Christopher W. ^{[1
]}

Evans, Jay T. ^{[1
]}

Johnson, David A. ^{[1
]}

机构：

[1] GlaxoSmithKline Biol, Hamilton, MT 59840 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 20期

关键词：

lipid A mimetics; TLR4; agonist; antagonist; AGP; glycolipids; immunostimulants; reductive alkylation;

D O I：

10.1016/j.bmcl.2008.09.060

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5350 / 5354

页数：5

共 32 条

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