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ID: ALA1152248
Journal: Bioorg Med Chem Lett
Title: The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics.
Authors: Bazin HG, Murray TJ, Bowen WS, Mozaffarian A, Fling SP, Bess LS, Livesay MT, Arnold JS, Johnson CL, Ryter KT, Cluff CW, Evans JT, Johnson DA.
Abstract: 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.
CiteXplore: 18835160