2. Academic Validation
  3. 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

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.
Shankar Venkatraman 1,  Alec D Lebsack,  Kenneth Alves,  Michael F Gardner,  Joyce James,  Russell B Lingham,  Salony Maniar,  Richard A Mumford,  Qian Si,  Nicholas Stock,  Kelly M Treonze,  Bowei Wang,  Jasmine Zunic,  Benito Munoz
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. p3ptide@yahoo.com
PMID: 19713111 DOI: 10.1016/j.bmcl.2009.07.111
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.

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