Novel p-Arylthio Cinnamides as Antagonists of Leukocyte Function-Associated Antigen-1/Intracellular Adhesion Molecule-1 Interaction. 2. Mechanism of Inhibition and Structure-Based Improvement of Pharmaceutical Properties

• Published in: Journal of medicinal chemistry Vol. 44; no. 8; pp. 1202 - 1210
• Main Authors: Liu, Gang, Huth, Jeffrey R, Olejniczak, Edward T, Mendoza, Renaldo, DeVries, Peter, Leitza, Sandra, Reilly, Edward B, Okasinski, Gregory F, Fesik, Stephen W, von Geldern, Thomas W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 12-04-2001
• Subjects: Allosteric Regulation; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Animals; Biological and medical sciences; Cinnamates - chemical synthesis; Cinnamates - chemistry; Cinnamates - pharmacokinetics; Combinatorial Chemistry Techniques; Immunomodulators; Intercellular Adhesion Molecule-1 - chemistry; Intercellular Adhesion Molecule-1 - physiology; Ligands; Lymphocyte Function-Associated Antigen-1 - chemistry; Lymphocyte Function-Associated Antigen-1 - physiology; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Rats; Solubility; Structure-Activity Relationship; Intravenous administration; Rat; Nitrogen heterocycle; Oxygen heterocycle; Organic sulfide; Structure activity relation; Chlorine Organic compounds; Area under the curve; Vinylic compound; Bicyclic compound; Aromatic compound; Inhibition; Chemical synthesis; Intercellular adhesion molecule 1; Immunomodulation; Rodentia; Oral administration; Bioavailability; Adhesion; Vertebrata; Mammalia; Animal; Carboxamide; Piperazine derivatives; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000503f

The interaction between leukocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory and immune diseases. Recently, a novel series of p-arylthio cinnamides has been described as potent antagonists of the LFA-1/ICAM-1 interaction. These compounds were found to bind to the I domain of LFA-1 using two-dimensional NMR spectroscopy of 15N-labeled LFA-1 I domain. On the basis of NOE studies between compound 1 and the I domain of LFA-1, a model of the complex was constructed. This model revealed that compound 1 does not directly inhibit ICAM-1 binding by interacting with the metal ion dependent adhesion site (MIDAS). Instead, it binds to the previously proposed I domain allosteric site (IDAS) of LFA-1 and likely modulates the activation of LFA-1 through its interaction with this regulatory site. A fragment-based NMR screening strategy was applied to identify small, more water-soluble ligands that bind to a specific region of the IDAS. When incorporated into the parent cinnamide template, the resulting analogues exhibited increased aqueous solubility and improved pharmacokinetic profiles in rats, demonstrating the power of this NMR-based screening approach for rapidly modifying high-affinity ligands.