The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics.
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.
GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
Hélène G
HG
Bazin
Tim J
TJ
Murray
William S
WS
Bowen
Afsaneh
A
Mozaffarian
Steven P
SP
Fling
Laura S
LS
Bess
Mark T
MT
Livesay
Jeffrey S
JS
Arnold
Craig L
CL
Johnson
Kendal T
KT
Ryter
Christopher W
CW
Cluff
Jay T
JT
Evans
David A
DA
Johnson
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006017:Glycolipids / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008050:Lipid A / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D009000:Monocytes / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C501717:CRX-526; D006017:Glycolipids; D008050:Lipid A; D008055:Lipids; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005944:Glucosamine