N-Tetrahydrofuroyl-(L)-phenylalanine derivatives as potent VLA-4 antagonists.
Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability.
Yang
Ginger X
GX
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. ginger_yang@merck.com
Chang
Linda L
LL
Truong
Quang
Q
Doherty
George A
GA
Magriotis
Plato A
PA
de Laszlo
Stephen E
SE
Li
Bing
B
MacCoss
Malcolm
M
Kidambi
Usha
U
Egger
Linda A
LA
McCauley
Ermengilda
E
Van Riper
Gail
G
Mumford
Richard A
RA
Schmidt
John A
JA
Hagmann
William K
WK
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D005663:Furans; D039041:Integrin alpha4beta1; D013449:Sulfonamides; D019010:Vascular Cell Adhesion Molecule-1; C018674:tetrahydrofuran; D010649:Phenylalanine