Abstract
We have shown that p-arylthio cinnamides can inhibit the interaction of LFA-1 and ICAM-1, which is involved in cell adhesion and the inflammatory process. We now show that 2,3-disubstitution on the aryl portion of the cinnamide results in enhanced activity over mono substitution on the ring. The best 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 and 40 which contain two CF3 groups have IC(50) values of 0.5 and 0.1 nM, respectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from adhering to ICAM-1. The structure-activity relationship (SAR) was examined using an NMR based model of the LFA-1 I domain/compound 31 complex. One of our compounds (38) was able to reduce cell migration in two different in vivo experiments.
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology
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Animals
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Cell Line
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Chemotaxis, Leukocyte / drug effects
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Cinnamates / chemical synthesis*
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Cinnamates / chemistry
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Cinnamates / pharmacology
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Enterotoxins / pharmacology
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Eosinophils / pathology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Intercellular Adhesion Molecule-1 / metabolism*
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Magnetic Resonance Spectroscopy
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Mice
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Models, Molecular
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Neutrophils / drug effects
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Neutrophils / physiology
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Ovalbumin / immunology
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Pneumonia / immunology
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Pneumonia / pathology
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Rats
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Staphylococcus aureus
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Structure-Activity Relationship
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacology
Substances
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(1-methylindol-5-yl)(2,3-dichloro-4-(((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl)sulfide
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Amides
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Cinnamates
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Enterotoxins
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Indoles
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Lymphocyte Function-Associated Antigen-1
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Sulfides
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Intercellular Adhesion Molecule-1
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enterotoxin A, Staphylococcal
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Ovalbumin