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

• Published in: Journal of medicinal chemistry 2001-12, Vol.44 (25), p.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: Article
• Language: English
• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0103108

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.