title: N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. gutterid@usna.mil
authors.forename: Clare E
authors.initials: CE
authors.lastname: Gutteridge
authors.forename: Stephen E
authors.initials: SE
authors.lastname: de Laszlo
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Ermengilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Gail
authors.initials: G
authors.lastname: van Riper
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Usha
authors.initials: U
authors.lastname: Kidambi
authors.forename: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Sharon
authors.initials: S
authors.lastname: Tong
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015815:Cell Adhesion Molecules; D006801:Humans; D007136:Immunoglobulins; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D009088:Mucoproteins / Q000037:antagonists & inhibitors; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000577:Amides; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D010649:Phenylalanine