Polycationic sulfonamides for the sequestration of endotoxin.
Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize the activity of LPS with high in vitro potency and afford complete protection in a murine model of endotoxic shock. Fatty acid amides of polyamines may be rapidly cleared from systemic circulation due to their susceptibility to nonspecific serum amidases and, thus, would be predicted to have a short duration of action. In a systematic effort to increase the likelihood of better bioavailability properties together with structural modifications that may result in gains in activity, we now report structure-activity relationships pertaining to endotoxin-binding and -neutralizing activities of homologated polyamine sulfonamides.
Burns
Mark R
MR
MediQuest Therapeutics, Inc., 22322 20th Avenue SE, Bothell, Washington 98021, USA. markburns@mqti.com
Jenkins
Scott A
SA
Kimbrell
Matthew R
MR
Balakrishna
Rajalakshmi
R
Nguyen
Thuan B
TB
Abbo
Benjamin G
BG
David
Sunil A
SA
D000818:Animals; D002412:Cations; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000506:poisoning; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D002412:Cations; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013449:Sulfonamides; D013096:Spermine; D009569:Nitric Oxide