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

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3380-2. doi: 10.1016/j.bmcl.2006.04.037. Epub 2006 May 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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

Substances

  • Amides
  • Collagen Type I
  • Integrin alpha2beta1