6533b857fe1ef96bd12b45a3

RESEARCH PRODUCT

A novel class of potent nonglycosidic and nonpeptidic pan-selectin inhibitors.

Einar E. ErikssonPhilip PrechAndreas LuxenburgerHolger UlbrichPierre RotziusGerd DannhardtOliver SoehnleinLennart Lindbom

subject

MaleModels MolecularInflammationEnzyme-Linked Immunosorbent AssayIn Vitro TechniquesPeritonitisLigandsMiceStructure-Activity RelationshipIn vivoDrug DiscoverymedicineCell AdhesionLeukocytespara-AminobenzoatesTetrasaccharideAnimalsIC50Binding SitesChemistryCell adhesion moleculeAnti-Inflammatory Agents Non-SteroidalCaseinsEndothelial CellsLigand (biochemistry)In vitroPeptide FragmentsMice Inbred C57BLBiochemistryAcute DiseaseSelectinsMolecular Medicinemedicine.symptomE-Selectin4-Aminobenzoic AcidSelectinAlgorithmsProtein Binding

description

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.

yearjournalcountryeditionlanguage
2006-09-29Journal of medicinal chemistry
10.1021/jm060468yhttps://pubmed.ncbi.nlm.nih.gov/17004713