Discovery of N-{N-[(3-cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(L)-prolyl}-4-[(3',5'-dichloroisonicotinoyl) amino]-(L)-phenylalanine (MK-0668), an extremely potent and orally active antagonist of very late antigen-4

J Med Chem. 2009 Jun 11;52(11):3449-52. doi: 10.1021/jm900257b.

Abstract

Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.

MeSH terms

  • Administration, Oral
  • Animals
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors
  • Dogs
  • Humans
  • Inhibitory Concentration 50
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemical synthesis
  • Niacinamide / pharmacokinetics
  • Niacinamide / pharmacology
  • Phenylalanine / administration & dosage
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemical synthesis
  • Phenylalanine / pharmacokinetics
  • Phenylalanine / pharmacology
  • Rats

Substances

  • Cytochrome P-450 CYP3A Inhibitors
  • Integrin alpha4beta1
  • N-(N-((3-cyanophenyl)sulfonyl)-4-cyclobutylaminoprolyl)-4-((3',5'-dichloroisonicotinoyl)amino)phenylalanine
  • Niacinamide
  • Phenylalanine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human