Discovery of Novel p-Arylthio Cinnamides as Antagonists of Leukocyte Function-Associated Antigen-1/Intercellular Adhesion Molecule-1 Interaction. 4. Structure−Activity Relationship of Substituents on the Benzene Ring of the Cinnamide

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 bes...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 44; no. 25; pp. 4393 - 4403
Main Authors:	Winn, Martin, Reilly, Edward B, Liu, Gang, Huth, Jeffrey R, Jae, Hwan-Soo, Freeman, Jennifer, Pei, Zhonghua, Xin, Zhili, Lynch, John, Kester, Jeff, von Geldern, Thomas W, Leitza, Sandra, DeVries, Peter, Dickinson, Robert, Mussatto, Donna, Okasinski, Gregory F
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 06-12-2001
Subjects:	Amides - chemical synthesis Amides - chemistry Amides - pharmacology Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cell Line Chemotaxis, Leukocyte - drug effects Cinnamates - chemical synthesis Cinnamates - chemistry Cinnamates - pharmacology Enterotoxins - pharmacology Eosinophils - pathology Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Intercellular Adhesion Molecule-1 - metabolism Lymphocyte Function-Associated Antigen-1 - metabolism Magnetic Resonance Spectroscopy Medical sciences Mice Models, Molecular Neutrophils - drug effects Neutrophils - physiology Ovalbumin - immunology Pharmacology. Drug treatments Pneumonia - immunology Pneumonia - pathology Rats Staphylococcus aureus Structure-Activity Relationship Sulfides - chemical synthesis Sulfides - chemistry Sulfides - pharmacology Endothelial cell Rat Nitrogen heterocycle Organic sulfide Structure activity relation Piperidine derivatives Bicyclic compound Aromatic compound Chemical synthesis Intercellular adhesion molecule 1 Rodentia Antiinflammatory agent Oral administration Inflammation Bioavailability Adhesion In vitro In vivo Vertebrata Experimental disease Mammalia Mouse Animal Carboxamide Benzenic compound Indole derivatives Pharmacokinetics
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Summary:	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 IC50 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.
Bibliography:	ark:/67375/TPS-NG1H4G7X-R istex:CA6209C572C93EB86F2A3ABBE5D3CD86E6BA8636 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm0103108