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

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.