Bioorganic & Medicinal Chemistry Letters 2002-02-25

Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists.

Ihor E Kopka, David N Young, Linus S Lin, Richard A Mumford, Plato A Magriotis, Malcolm MacCoss, Sander G Mills, Gail Van Riper, Ermengilda McCauley, Linda E Egger, Usha Kidambi, John A Schmidt, Kathryn Lyons, Ralph Stearns, Stella Vincent, Adria Colletti, Zhen Wang, Sharon Tong, Junying Wang, Song Zheng, Karen Owens, Dorothy Levorse, William K Hagmann

Index: Bioorg. Med. Chem. Lett. 12(4) , 637-40, (2002)

Full Text: HTML

Abstract

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.