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

The novel ether lipid AGPs 4 and 5 were synthesized by a highly convergent method and evaluated along with their ester counterparts for TLR4 activity in both in vitro and in vivo models. Unlike agonist 4, compound 5 showed species-specific agonist/antagonist activity. 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.