How natalizumab binds and antagonizes α4 integrins

  • Leone D
  • Giza K
  • Gill A
 et al. 
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Abstract

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics. ?? 2009 Elsevier Ltd. All rights reserved.

Author-supplied keywords

  • ??-Amino acid
  • ??4??1
  • Amino Acid Sequence
  • Anti-inflammatory
  • Autoimmune
  • Bicyclic
  • Binding
  • Binding Sites
  • Bioavailable
  • Cell Adhesion
  • Cell Adhesion Molecules
  • Cell Adhesion Molecules: metabolism
  • Competitive
  • Conformational restriction
  • Fibronectin
  • Fibronectin: metabolism
  • Fibronectins
  • Fibronectins: metabolism
  • Firategrast
  • Humans
  • Integrin
  • Integrin alpha4beta1
  • Integrin antagonists
  • Integrins
  • Integrins: metabolism
  • Kinetics
  • Ligands
  • Lymphocytes
  • Molecular Sequence Data
  • Multiple sclerosis
  • Peptides
  • Peptides: chemistry
  • Peptides: metabolism
  • Progressive multifocal leukoencephalopathy
  • Protein Binding
  • Receptors
  • Small-molecule inhibitors
  • VLA-4 antagonists
  • Vascular Cell Adhesion Molecule-1
  • enantiomers
  • inflammation
  • integrin ligands
  • peptidomimetics

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Authors

  • Diane R Leone

  • K Giza

  • Alan Gill

  • B M Dolinski

  • W Yang

  • S Perper

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