Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Aminobenzoic Acid / chemical synthesis
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4-Aminobenzoic Acid / chemistry
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4-Aminobenzoic Acid / pharmacology
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Acute Disease
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Algorithms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Binding Sites
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Caseins
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Cell Adhesion / drug effects
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E-Selectin / metabolism
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Endothelial Cells / physiology
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Enzyme-Linked Immunosorbent Assay
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In Vitro Techniques
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Leukocytes / physiology
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Ligands
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Male
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Peptide Fragments
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Peritonitis / chemically induced
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Peritonitis / drug therapy
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Protein Binding
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Selectins / metabolism*
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Structure-Activity Relationship
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para-Aminobenzoates*
Substances
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4-(N-(6-(3,5-bis(decyloxy)phenoxy)hexyl)-N-(4-carboxyphenyl)amino)benzoic acid
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Anti-Inflammatory Agents, Non-Steroidal
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Caseins
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E-Selectin
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Ligands
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Peptide Fragments
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Selectins
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para-Aminobenzoates
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proteose-peptone
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4-Aminobenzoic Acid