Discovery of Potent Antagonists of Leukocyte Function-Associated Antigen-1/Intercellular Adhesion Molecule-1 Interaction. 3. Amide (C-Ring) Structure−Activity Relationship and Improvement of Overall Properties of Arylthio Cinnamides

• Published in: Journal of medicinal chemistry Vol. 44; no. 18; pp. 2913 - 2920
• Main Authors: Pei, Zhonghua, Xin, Zhili, Liu, Gang, Li, Yihong, Reilly, Edward B, Lubbers, Nathan L, Huth, Jeffery R, Link, James T, von Geldern, Thomas W, Cox, Bryan F, Leitza, Sandra, Gao, Yi, Marsh, Kennan C, DeVries, Peter, Okasinski, Greg F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.08.2001; Amer Chemical Soc
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Animals; Biological and medical sciences; Cardiovascular Agents - chemical synthesis; Cardiovascular Agents - chemistry; Cardiovascular Agents - pharmacokinetics; Cardiovascular Agents - pharmacology; Cardiovascular system; Cell Adhesion - drug effects; Cell Line; Chemistry, Medicinal; Cinnamates - chemical synthesis; Cinnamates - chemistry; Cinnamates - pharmacokinetics; Cinnamates - pharmacology; Intercellular Adhesion Molecule-1 - metabolism; Life Sciences & Biomedicine; Lymphocyte Function-Associated Antigen-1 - metabolism; Magnetic Resonance Spectroscopy; Male; Medical sciences; Miscellaneous; Models, Molecular; Myocardial Infarction - pathology; Myocardium - pathology; Nipecotic Acids - chemical synthesis; Nipecotic Acids - chemistry; Nipecotic Acids - pharmacokinetics; Nipecotic Acids - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Science & Technology; Solubility; Structure-Activity Relationship; Sulfides - chemical synthesis; Sulfides - chemistry; Sulfides - pharmacokinetics; Sulfides - pharmacology; SITE; INJURY; MONOCLONAL-ANTIBODY; CELL-ADHESION; A-DOMAIN; INHIBITORS; ISCHEMIA-REPERFUSION; I-DOMAIN; RECEPTOR ANTAGONIST; ADHERENCE; Intravenous administration; Infarct; Rat; Nitrogen heterocycle; Size; Cardiovascular disease; Binding site; Oxygen heterocycle; Modeling; Myocardial disease; Organic sulfide; Reduction; Reperfusion; Ischemia; Structure activity relation; Vinylic compound; Molecular model; Bicyclic compound; Aromatic compound; Chemical synthesis; Dog; Fissipedia; Carnivora; Intercellular adhesion molecule 1; Rodentia; Benzene derivatives; Cardioprotective agent; Cell adhesion molecule; Oral administration; Bioavailability; Adhesion; Coronary heart disease; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Aminoacid; Animal; Myocardium; Carboxamide; Inhibitor; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010059w

The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.