Arylamide derivatives as allosteric inhibitors of the integrin alpha2beta1/type I collagen interaction

We herein report a group of allosteric inhibitors of integrin alpha(2)beta(1) based on an arylamide scaffold. Compound 4 showed an IC(50) of 4.80 microM in disrupting integrin I-domain/collagen binding in an ELISA. These arylamide compounds are able to block collagen binding to integrin alpha(2)beta...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2006-07, Vol.16 (13), p.3380-3382
Hauptverfasser:	Yin, Hang, Gerlach, Lars Ole, Miller, Meredith W, Moore, David T, Liu, Dahui, Vilaire, Gaston, Bennett, Joel S, DeGrado, William F
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation Amides - chemistry Amides - pharmacology Binding Sites - drug effects Collagen Type I - antagonists & inhibitors Collagen Type I - metabolism Enzyme-Linked Immunosorbent Assay Humans Hydrophobic and Hydrophilic Interactions Integrin alpha2beta1 - antagonists & inhibitors Integrin alpha2beta1 - metabolism Magnetic Resonance Spectroscopy - methods Models, Molecular Molecular Structure Protein Binding - drug effects Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	We herein report a group of allosteric inhibitors of integrin alpha(2)beta(1) based on an arylamide scaffold. Compound 4 showed an IC(50) of 4.80 microM in disrupting integrin I-domain/collagen binding in an ELISA. These arylamide compounds are able to block collagen binding to integrin alpha(2)beta(1) on the platelet surface. Further we find that compound 4 recognizes a hydrophobic cleft on the side of the alpha(2) I-domain, suggesting an alternative targeting site for drug development.
ISSN:	0960-894X