Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists.
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl- and (L)-azetidyl-beta-biaryl beta-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins.
Kopka
Ihor E
IE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. ihor_kopka@merck.com
Lin
Linus S
LS
Mumford
Richard A
RA
Lanza
Thomas
T
Magriotis
Plato A
PA
Young
David
D
DeLaszlo
Stephen E
SE
MacCoss
Malcolm
M
Mills
Sander G
SG
Van Riper
Gail
G
McCauley
Ermengilda
E
Lyons
Kathryn
K
Vincent
Stella
S
Egger
Linda A
LA
Kidambi
Usha
U
Stearns
Ralph
R
Colletti
Adria
A
Teffera
Yohannes
Y
Tong
Sharon
S
Owens
Karen
K
Levorse
Dorothy
D
Schmidt
John A
JA
Hagmann
William K
WK
D000284:Administration, Oral; D000409:Alanine / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D019169:Jurkat Cells; D008657:Metabolic Clearance Rate; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D011422:Propionates; D019010:Vascular Cell Adhesion Molecule-1; D000409:Alanine