N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists

Clare E Gutteridge; Stephen E de Laszlo; Theodore M Kamenecka; Ermengilda McCauley; Gail van Riper; Richard A Mumford; Usha Kidambi; Linda A Egger; Sharon Tong; William K Hagmann

doi:10.1016/s0960-894x(02)01077-6

N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists

Bioorg Med Chem Lett. 2003 Mar 10;13(5):885-90. doi: 10.1016/s0960-894x(02)01077-6.

Authors

Clare E Gutteridge¹, Stephen E de Laszlo, Theodore M Kamenecka, Ermengilda McCauley, Gail van Riper, Richard A Mumford, Usha Kidambi, Linda A Egger, Sharon Tong, William K Hagmann

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. gutterid@usna.mil

PMID: 12617914
DOI: 10.1016/s0960-894x(02)01077-6

Abstract

The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4 integrin, was investigated. This effort resulted in the identification of N-(3-phenylsulfonyl-3-piperidinoyl)-(L)-4-(2',6'-dimethoxyphenyl)phenylalanine 52 as a potent, selective VLA-4 antagonist (IC(50)=90 pM). Expansion of the SAR demonstrated that this structural unit can be used to identify a diverse series of sub-nanomolar antagonists.

MeSH terms

Amides / chemistry
Amides / metabolism
Amides / pharmacology
Cell Adhesion Molecules
Humans
Immunoglobulins
Inhibitory Concentration 50
Integrin alpha4beta1 / antagonists & inhibitors*
Integrin alpha4beta1 / metabolism
Jurkat Cells
Mucoproteins / antagonists & inhibitors
Phenylalanine / analogs & derivatives*
Phenylalanine / pharmacokinetics
Phenylalanine / pharmacology*
Radioligand Assay
Receptors, Lymphocyte Homing / antagonists & inhibitors
Structure-Activity Relationship
Vascular Cell Adhesion Molecule-1 / metabolism

Substances

Amides
Cell Adhesion Molecules
Immunoglobulins
Integrin alpha4beta1
MADCAM1 protein, human
Mucoproteins
Receptors, Lymphocyte Homing
Vascular Cell Adhesion Molecule-1
Phenylalanine