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

J Med Chem. 2001 Dec 6;44(25):4393-403. doi: 10.1021/jm0103108.

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

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • 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
  • Mice
  • Models, Molecular
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Ovalbumin / immunology
  • Pneumonia / immunology
  • Pneumonia / pathology
  • Rats
  • Staphylococcus aureus
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis*
  • Sulfides / chemistry
  • Sulfides / pharmacology

Substances

  • (1-methylindol-5-yl)(2,3-dichloro-4-(((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl)sulfide
  • Amides
  • Cinnamates
  • Enterotoxins
  • Indoles
  • Lymphocyte Function-Associated Antigen-1
  • Sulfides
  • Intercellular Adhesion Molecule-1
  • enterotoxin A, Staphylococcal
  • Ovalbumin