Discovery of N-{N-[(3-cyanobenzene) sulfonyl]-4(R)-(3,3-difluoropiperidin-1-yl)-(l)-prolyl}-4-[(3',5'-dichloro-isonicotinoyl) amino]-(l)-phenylalanine (MK-0617), a highly potent and orally active VLA-4 antagonist

Bioorg Med Chem Lett. 2009 Oct 1;19(19):5803-6. doi: 10.1016/j.bmcl.2009.07.111. Epub 2009 Jul 28.

Abstract

A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats.

MeSH terms

  • Administration, Oral
  • Animals
  • Dipeptides / administration & dosage
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Drug Discovery
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Integrin alpha4beta1 / metabolism
  • Phenylalanine / administration & dosage
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemical synthesis
  • Prodrugs / administration & dosage
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry*
  • Rats

Substances

  • Dipeptides
  • Integrin alpha4beta1
  • N-(N-((3-cyanobenzene)sulfonyl)-4-(3,3-difluoropiperidin-1-yl)prolyl)-4-((3',5'-dichloroisonicotinoyl)amino)-phenylalanine
  • Prodrugs
  • Phenylalanine