A novel class of potent nonglycosidic and nonpeptidic pan-selectin inhibitors.
An early step of the inflammatory response, the rolling of leukocytes on activated endothelial cells, is mediated by selectin/carbohydrate interactions. The tetrasaccharide sialy Lewisx is a ligand for E-, P-, and L-selectin and therefore serves as a lead structure for the development of analogues. A combination of synthesis and structure-based design allowed rapid optimization. The current lead 2a was evaluated in our E-selectin cell flow chamber assay where it proved to inhibit rolling and adhesion with an IC50 of 28+/-7 microM. The assays used are predictive for the in vivo efficacy of test compounds as shown for 2a in a proteose peptone induced peritonitis model of acute inflammation in mice.
Ulbrich
Holger K
HK
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Johannes Gutenberg University, Staudingerweg 5, DE-55099 Mainz, Germany. ulbrich@uni-mainz.de
Luxenburger
Andreas
A
Prech
Philip
P
Eriksson
Einar E
EE
Soehnlein
Oliver
O
Rotzius
Pierre
P
Lindbom
Lennart
L
Dannhardt
Gerd
G
D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000208:Acute Disease; D000465:Algorithms; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002364:Caseins; D002448:Cell Adhesion / Q000187:drug effects; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D066298:In Vitro Techniques; D007962:Leukocytes / Q000502:physiology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010446:Peptide Fragments; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D011485:Protein Binding; D019087:Selectins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
C514370:4-(N-(6-(3,5-bis(decyloxy)phenoxy)hexyl)-N-(4-carboxyphenyl)amino)benzoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002364:Caseins; D019040:E-Selectin; D008024:Ligands; D010446:Peptide Fragments; D019087:Selectins; D062366:para-Aminobenzoates; C018135:proteose-peptone; D010129:4-Aminobenzoic Acid