Abstract
LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency.
MeSH terms
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Animals
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Drug Design
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Intercellular Adhesion Molecule-1 / drug effects*
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Lymphocyte Function-Associated Antigen-1 / drug effects*
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Male
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Molecular Conformation
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Phenols / chemical synthesis*
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Phenols / chemistry
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Phenols / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Tyrosine / chemistry
Substances
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Lymphocyte Function-Associated Antigen-1
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Phenols
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Intercellular Adhesion Molecule-1
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Tyrosine