N-Cycloalkanoyl- l-Phenylalanine Derivatives as VCAM/VLA-4 Antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 17; pp. 2475 - 2478
• Main Authors: Sidduri, Achyutharao, Tilley, Jefferson W, Hull, Kenneth, Ping Lou, Jian, Kaplan, Gerry, Sheffron, Allen, Chen, Li, Campbell, Robert, Guthrie, Robert, Huang, Tai-Nan, Huby, Nicholas, Rowan, Karen, Schwinge, Virginia, Renzetti, Louis M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02.09.2002; Elsevier
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Crystallography, X-Ray; Cycloparaffins - chemical synthesis; Cycloparaffins - pharmacology; Humans; Inhibitory Concentration 50; Integrin alpha4beta1 - antagonists & inhibitors; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Protein Binding; Structure-Activity Relationship; Vascular Cell Adhesion Molecule-1 - drug effects; Vascular cell adhesion molecule 1; Molecular structure; Cycloalkane; Thioureas; Adhesion; In vitro; α-Aminoacid; Integrin; Structure activity relation; Chlorine Organic compounds; Benzamide derivatives; Carboxamide; Ureas; Inhibitor; Antagonist; Chemical synthesis; Biological receptor; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00386-4

A systematic structure–activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]- l-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (−) bioactive conformation. A systematic structure–activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]- l-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (−) bioactive conformation.