Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists.
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.
Kopka
Ihor E
IE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. ihor_kopka@merck.com
Young
David N
DN
Lin
Linus S
LS
Mumford
Richard A
RA
Magriotis
Plato A
PA
MacCoss
Malcolm
M
Mills
Sander G
SG
Van Riper
Gail
G
McCauley
Ermengilda
E
Egger
Linda E
LE
Kidambi
Usha
U
Schmidt
John A
JA
Lyons
Kathryn
K
Stearns
Ralph
R
Vincent
Stella
S
Colletti
Adria
A
Wang
Zhen
Z
Tong
Sharon
S
Wang
Junying
J
Zheng
Song
S
Owens
Karen
K
Levorse
Dorothy
D
Hagmann
William K
WK
D000818:Animals; D001682:Biological Availability; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D000882:Haplorhini; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008657:Metabolic Clearance Rate; D010649:Phenylalanine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013329:Structure-Activity Relationship; D013450:Sulfones; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects
D004151:Dipeptides; D039041:Integrin alpha4beta1; D013450:Sulfones; D019010:Vascular Cell Adhesion Molecule-1; D010649:Phenylalanine; C010544:benzenesulfonyl chloride