title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. p3ptide@yahoo.com
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Alec D
authors.initials: AD
authors.lastname: Lebsack
authors.forename: Kenneth
authors.initials: K
authors.lastname: Alves
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.forename: Salony
authors.initials: S
authors.lastname: Maniar
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Qian
authors.initials: Q
authors.lastname: Si
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stock
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Treonze
authors.forename: Bowei
authors.initials: B
authors.lastname: Wang
authors.forename: Jasmine
authors.initials: J
authors.lastname: Zunic
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004151:Dipeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D055808:Drug Discovery; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats
chemical_list: D004151:Dipeptides; D039041:Integrin alpha4beta1; C545116:N-(N-((3-cyanobenzene)sulfonyl)-4-(3,3-difluoropiperidin-1-yl)prolyl)-4-((3',5'-dichloroisonicotinoyl)amino)-phenylalanine; D011355:Prodrugs; D010649:Phenylalanine