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.
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.
Venkatraman
Shankar
S
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. p3ptide@yahoo.com
Lebsack
Alec D
AD
Alves
Kenneth
K
Gardner
Michael F
MF
James
Joyce
J
Lingham
Russell B
RB
Maniar
Salony
S
Mumford
Richard A
RA
Si
Qian
Q
Stock
Nicholas
N
Treonze
Kelly M
KM
Wang
Bowei
B
Zunic
Jasmine
J
Munoz
Benito
B
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
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