title: Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. ihor_kopka@merck.com
authors.forename: Ihor E
authors.initials: IE
authors.lastname: Kopka
authors.forename: David N
authors.initials: DN
authors.lastname: Young
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Plato A
authors.initials: PA
authors.lastname: Magriotis
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Gail
authors.initials: G
authors.lastname: Van Riper
authors.forename: Ermengilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Linda E
authors.initials: LE
authors.lastname: Egger
authors.forename: Usha
authors.initials: U
authors.lastname: Kidambi
authors.forename: John A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Ralph
authors.initials: R
authors.lastname: Stearns
authors.forename: Stella
authors.initials: S
authors.lastname: Vincent
authors.forename: Adria
authors.initials: A
authors.lastname: Colletti
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Sharon
authors.initials: S
authors.lastname: Tong
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.forename: Karen
authors.initials: K
authors.lastname: Owens
authors.forename: Dorothy
authors.initials: D
authors.lastname: Levorse
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000818:Animals; D001682:Biological Availability; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D000882:Haplorhini; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008657:Metabolic Clearance Rate; D010649:Phenylalanine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013329:Structure-Activity Relationship; D013450:Sulfones; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects
chemical_list: D004151:Dipeptides; D039041:Integrin alpha4beta1; D013450:Sulfones; D019010:Vascular Cell Adhesion Molecule-1; D010649:Phenylalanine; C010544:benzenesulfonyl chloride