N-aryl-prolyl-dipeptides as potent antagonists of VLA-4.
The design, synthesis, and biological evaluation of N-arylprolyl-dipeptide derivatives as small molecule VLA-4 antagonists is described. Potency against VLA-4 and alpha(4)beta(7) and rat pharmacokinetic evaluation revealed some advantages over the related N-(arylsulfonyl)-prolyl-dipeptide analogues.
Kamenecka
Theodore M
TM
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. theodore_kamenecka@merck.com
Lanza
Thomas
T
de Laszlo
Stephen E
SE
Li
Bing
B
McCauley
Ermengilda D
ED
Van Riper
Gail
G
Egger
Linda A
LA
Kidambi
Usha
U
Mumford
Richard A
RA
Tong
Sharon
S
MacCoss
Malcolm
M
Schmidt
John A
JA
Hagmann
William K
WK
D000818:Animals; D004151:Dipeptides / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D004151:Dipeptides; D039041:Integrin alpha4beta1