Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists

Ihor E Kopka; Linus S Lin; Richard A Mumford; Thomas Lanza Jr; Plato A Magriotis; David Young; Stephen E DeLaszlo; Malcolm MacCoss; Sander G Mills; Gail Van Riper; Ermengilda McCauley; Kathryn Lyons; Stella Vincent; Linda A Egger; Usha Kidambi; Ralph Stearns; Adria Colletti; Yohannes Teffera; Sharon Tong; Karen Owens; Dorothy Levorse; John A Schmidt; William K Hagmann

doi:10.1016/s0960-894x(02)00460-2

Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists

Bioorg Med Chem Lett. 2002 Sep 2;12(17):2415-8. doi: 10.1016/s0960-894x(02)00460-2.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]

PMID: 12161146
DOI: 10.1016/s0960-894x(02)00460-2

Abstract

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.

MeSH terms

Administration, Oral
Alanine / chemical synthesis
Alanine / pharmacokinetics
Alanine / pharmacology
Biological Availability
Humans
Inhibitory Concentration 50
Integrin alpha4beta1 / antagonists & inhibitors*
Jurkat Cells
Metabolic Clearance Rate
Propionates / chemical synthesis*
Propionates / pharmacokinetics
Propionates / pharmacology
Protein Binding
Structure-Activity Relationship
Vascular Cell Adhesion Molecule-1 / metabolism

Substances

Integrin alpha4beta1
Propionates
Vascular Cell Adhesion Molecule-1
Alanine