title: Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists.
abstract: A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. george_doherty@merck.com
authors.forename: George A
authors.initials: GA
authors.lastname: Doherty
authors.forename: Ginger X
authors.initials: GX
authors.lastname: Yang
authors.forename: Edite
authors.initials: E
authors.lastname: Borges
authors.forename: Linda L
authors.initials: LL
authors.lastname: Chang
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Sharon
authors.initials: S
authors.lastname: Tong
authors.forename: Usha
authors.initials: U
authors.lastname: Kidambi
authors.forename: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Ermenegilda
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: John A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008024:Ligands; D008970:Molecular Weight; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D005663:Furans; D039041:Integrin alpha4beta1; D008024:Ligands; D013449:Sulfonamides; D019010:Vascular Cell Adhesion Molecule-1; C018674:tetrahydrofuran; D010649:Phenylalanine